EP1687043A2 - Electrical devices and anti-scarring agents - Google Patents

Electrical devices and anti-scarring agents

Info

Publication number
EP1687043A2
EP1687043A2 EP04811760A EP04811760A EP1687043A2 EP 1687043 A2 EP1687043 A2 EP 1687043A2 EP 04811760 A EP04811760 A EP 04811760A EP 04811760 A EP04811760 A EP 04811760A EP 1687043 A2 EP1687043 A2 EP 1687043A2
Authority
EP
European Patent Office
Prior art keywords
medical device
agent
inhibitor
coating
scarring
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04811760A
Other languages
German (de)
English (en)
French (fr)
Inventor
William L. Hunter
David M. Gravett
Philip M. Toleikis
Arpita Maiti
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Angiotech International AG
Original Assignee
Angiotech International AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/986,230 external-priority patent/US20050148512A1/en
Priority claimed from US10/986,231 external-priority patent/US20050181977A1/en
Application filed by Angiotech International AG filed Critical Angiotech International AG
Publication of EP1687043A2 publication Critical patent/EP1687043A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/372—Arrangements in connection with the implantation of stimulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/432—Inhibitors, antagonists
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/45—Mixtures of two or more drugs, e.g. synergistic mixtures

Definitions

  • the present invention relates generally to pharmaceutical compositions, methods and devices, and more specifically, to compositions and methods for preparing and using medical implants to make them resistant to overgrowth by inflammatory, fibrous and glial scar tissue.
  • Medical devices having electrical components can be implanted in the body to provide electrical conduction to the central and peripheral nervous system (including the autonomic system), cardiac muscle tissue (including myocardial conduction pathways), smooth muscle tissue and skeletal muscle tissue.
  • These electrical impulses are used to treat many bodily dysfunctions and disorders by blocking, masking, stimulating, or replacing electrical signals within the body.
  • Examples include pacemaker leads used to maintain the normal rhythmic beating of the heart; defibrillator leads used to "re-start” the heart when it stops beating; peripheral nerve stimulating devices to treat chronic pain; deep brain electrical stimulation to treat conditions such as tremor, Parkinson's disease, movement disorders, epilepsy, depression and psychiatric disorders; and vagal nerve stimulation to treat epilepsy, depression, anxiety, obesity, migraine and Alzheimer's Disease.
  • the clinical function of an electrical device such as a cardiac pacemaker lead, neurostimulation lead, or other electrical lead depends upon the device being able to effectively maintain intimate anatomical contact with the target tissue (typically electrically excitable cells such as muscle or nerve) such that electrical conduction from the device to the tissue can occur.
  • fibrous encapsulation of the device can occur even after a successful implantation if the device is manipulated (some patients continuously "fiddle" with a subcutaneous implant) or irritated by the daily activities of the patient.
  • the electrical characteristics of the electrode-tissue interface degrade, and the device may fail to function properly. For example, it may require additional electrical current from the lead to overcome the extra resistance imposed by the intervening scar (or glial) tissue. This can shorten the battery life of an implant (making more frequent removal and re-implantation necessary), prevent electrical conduction altogether (rendering the implant clinically ineffective) and/or cause damage to the target tissue.
  • the surrounding tissue may be inadvertently damaged from the inflammatory foreign body response, which can result in loss of function or tissue necrosis.
  • the present invention discloses pharmaceutical agents which inhibit one or more aspects of the production of excessive fibrous (scar) or glial tissue.
  • the present invention provides compositions for delivery of selected therapeutic agents via medical implants or implantable electrical medical devices, as well as methods for making and using these implants and devices.
  • Compositions and methods are described for coating electrical medical devices and implants with drug-delivery compositions such that the pharmaceutical agent is delivered in therapeutic levels over a period sufficient to prevent the device electrode from being encapsulated in fibrous or glial tissue and to allow normal electrical conduction to occur.
  • compositions e.g., topicals, injectables, liquids, gels, sprays, microspheres, pastes, wafers
  • an inhibitor of fibrosis or gliosis
  • numerous specific cardiac and neurological implants and devices are described that produce superior clinical results as a result of being coated with agents that reduce excessive scarring and fibrous (or glial) tissue accumulation as well as other related advantages.
  • drug-coated or drug- impregnated implants and medical devices which reduce fibrosis or gliosis in the tissue surrounding the electrical device or implant, or inhibit scar development on the device/implant surface (particularly the electrical lead), thus enhancing the efficacy of the procedure.
  • it may require additional electrical current from the lead to overcome the extra resistance imposed by the intervening scar (or glial) tissue. This can shorten the battery life of an implant (making more frequent removal and re-implantation necessary), prevent electrical conduction altogether (rendering the implant clinically ineffective) and/or cause damage to the target tissue.
  • fibrosis or gliosis is inhibited by local or systemic release of specific pharmacological agents that become localized to the adjacent tissue.
  • the repair of tissues following a mechanical or surgical intervention, such as the implantation of an electrical device involves two distinct processes: (1 ) regeneration (the replacement of injured cells by cells of the same type and (2) fibrosis (the replacement of injured cells by connective tissue).
  • There are four general components to the process of fibrosis (or scarring) including: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts or smooth muscle cells), deposition of extracellular matrix (ECM), and remodeling (maturation and organization of the fibrous tissue).
  • inhibitors (reduces) fibrosis should be understood to refer to agents or compositions which decrease or limit the formation of fibrous tissue (i.e., by reducing or inhibiting one or more of the processes of angiogenesis, connective tissue cell migration or proliferation, ECM production, and/or remodeling).
  • numerous therapeutic agents described in this invention may have the additional benefit of also reducing tissue regeneration where appropriate. It should be noted that in implantation procedures that cause injuries to the central nervous system (CNS), fibrosis is replaced by a process called gliosis (the replacement of injured or dead cells with glial tissue).
  • Glial cells form the supporting tissue of the CNS and are comprised of macroglia (astrocytes, oligodendrocytes, ependyma cells) and microglia cells. Of these cell types, astrocytes are the principle cells responsible for repair and scar formation in the brain and spinal cord. Gliosis is the most important indicator of CNS damage and consists of astrocyte hypertrophy (increase in size) and hyperplasia (increase in cell number as a result of cell division) in response to injury or trauma, such as that caused by the implantation of a medical device.
  • Astrocytes are responsible for phagocytosing dead or damaged tissue and repairing the injury with glial tissue and thus, serve a similar role to that performed by fibroblasts in scarring outside the brain.
  • astrocytes gliosis
  • an implant or device is adapted to release an agent that inhibits fibrosis or gliosis through one or more of the mechanisms sited herein.
  • an implant or device contains an agent that while remaining associated with the implant or device, inhibits fibrosis between the implant or device and the tissue where the implant or device is placed by direct contact between the agent and the tissue surrounding the implant or device.
  • cardiac and neurostimulation devices are provided comprising an implant or device, wherein the implant or device releases an agent which inhibits fibrosis (or gliosis) in vivo.
  • Release of an agent refers to any statistically significant presence of the agent, or a subcomponent thereof, which has disassociated from the implant/device and/or remains active on the surface of (or within) the device/implant.
  • a medical device or implant comprising the step of coating (e.g., spraying, dipping, wrapping, or administering drug through) a medical device or implant.
  • the implant or medical device can be constructed so that the device itself is comprised of materials which inhibit fibrosis in or around the implant.
  • electrical medical devices and implants may be utilized within the context of the present invention, depending on the site and nature of treatment desired.
  • the implant or device is further coated with a composition or compound, which delays the onset of activity of the fibrosis-inhibiting (or gliosis-inhibiting) agent for a period of time after implantation.
  • the fibrosis-inhibiting (or gliosis-inhibiting) implant or device is activated before, during, or after deployment (e.g., an inactive agent on the device is first activated to one that reduces or inhibits an in vivo fibrotic or gliotic reaction).
  • an inactive agent on the device is first activated to one that reduces or inhibits an in vivo fibrotic or gliotic reaction.
  • the tissue surrounding the implant or device is treated with a composition or compound that contains an inhibitor of fibrosis or gliosis.
  • compositions e.g., topicals, injectables, liquids, gels, sprays, microspheres, pastes, wafers
  • compounds containing an inhibitor of fibrosis or gliosis
  • This can be done in lieu of coating the device or implant with a fibrosis/gliosis-inhibitor, or done in addition to coating the device or implant with a fibrosis/gliosis-inhibitor.
  • an electrical device or implant is coated on one aspect, portion or surface with a composition which inhibits fibrosis, as well as being coated with a composition or compound which promotes scarring on another aspect, portion or surface of the device (i.e., to affix the body of the device into a particular anatomical space).
  • agents that promote fibrosis and scarring include silk, silica, crystalline silicates, bleomycin, quartz dust, neomycin, talc, metallic beryllium and oxides thereof, retinoic acid compounds, copper, leptin, growth factors, a component of extracellular matrix; fibronectin, collagen, fibrin, or fibrinogen, polylysine, poly(ethylene-co-vinylacetate), chitosan, N-carboxybutylchitosan, and RGD proteins; vinyl chloride or a polymer of vinyl chloride; an adhesive selected from the group consisting of cyanoacrylates and crosslinked poly( ethylene glycol) - methylated collagen; an inflammatory cytokine (e.g., TGF ⁇ , PDGF, VEGF, bFGF, TNF ⁇ , NGF, GM-CSF, IGF-1 , IL-1 , IL-1- ⁇ , IL-8, IL- 6, and growth hormone); connective tissue growth factor (
  • Also provided by the present invention are methods for treating patients undergoing surgical, endoscopic or minimally invasive therapies where an electrical device or implant is placed as part of the procedure.
  • inhibits fibrosis or gliosis refers to a statistically significant decrease in the amount of scar tissue in or around the device or an improvement in the interface between the electrical device or implant and the tissue, which may or may not lead to a permanent prohibition of any complications or failures of the device/implant.
  • the pharmaceutical agents and compositions are utilized to create novel drug-coated implants and medical devices that reduce the foreign body response to implantation and limit the growth of reactive tissue on the surface of, or around in the tissue surrounding the device, such that performance is enhanced.
  • the present invention is directed to electrical stimulatory devices that comprise a medical implant and at least one of (i) an anti-scarring agent and (ii) a composition that comprises an anti- scarring agent.
  • the agent is present so as to inhibit scarring that may otherwise occur when the implant is placed within an animal.
  • the present invention is directed to methods wherein both an implant and at least one of (i) an anti-scarring agent and (ii) a composition that comprises an anti-scarring agent, are placed into an animal, and the agent inhibits scarring that may otherwise occur.
  • the present invention provides a device, comprising a cardiac or neurostimulator implant and an anti- scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring.
  • the present invention provides that: the agent is a cell cycle inhibitor; the agent is an anthracycline; the agent is a taxane; the agent is a podophyllotoxin; the agent is an immunomodulator; the agent is a heat shock protein 90 antagonist; the agent is a HMGCoA reductase inhibitor; the agent is an inosine monophosphate dehydrogenase inhibitor; the agent is an NF kappa B inhibitor; the agent is a P38 MAP kinase inhibitor.
  • the agent may be present in a composition along with a polymer.
  • the polymer is biodegradable.
  • the polymer is non- biodegradable.
  • the present invention provides methods whereby a specified device is implanted into an animal, and a specified agent associated with the device inhibits scarring (or gliosis) that may otherwise occur.
  • a specified device may be a "specified device”
  • each of the anti-scarring agents identified herein may be an "anti-scarring agent” where the present invention provides, in independent embodiments, for each possible combination of the device and the agent.
  • the agent may be associated with the device prior to the device being placed within the animal.
  • the agent may be coated onto an implant, and the resulting device then placed within the animal.
  • the agent may be independently placed within the animal in the vicinity of where the device is to be, or is being, placed within the animal.
  • the agent may be sprayed or otherwise placed onto, adjacent to, and/or within the tissue that will be contacting the medical implant or may otherwise undergo scarring.
  • the present invention provides placing a cardiac or neurostimulation implant and an anti-scarring (or anti-gliosis) agent or a composition comprising an anti-scarring (or anti-gliosis) agent into an animal host, wherein the agent inhibits scarring or gliosis.
  • the present invention provides that: the agent is a cell cycle inhibitor; the agent is an anthracycline; the agent is a taxane; the agent is a podophyllotoxin; the agent is an immunomodulator; the agent is a heat shock protein 90 antagonist; the agent is a HMGCoA reductase inhibitor; the agent is an inosine monophosphate dehydrogenase inhibitor; the agent is an NF kappa B inhibitor; the agent is a P38 MAP kinase inhibitor.
  • the agent may be present in a composition along with a polymer.
  • the polymer is biodegradable.
  • the polymer is non-biodegradable.
  • Figure 1 is a diagram showing how a cell cycle inhibitor acts at one or more of the steps in the biological pathway.
  • Figure 2 is a graph showing the results for the screening assay for assessing the effect of mitoxantrone on nitric oxide production by THP-1 macrophages.
  • Figure 3 is a graph showing the results for the screening assay for assessing the effect of Bay 11-7082 on TNF-alpha production by THP-1 macrophages.
  • Figure 4 is a graph showing the results for the screening assay for assessing the effect of rapamycin concentration for TNF ⁇ production by THP-1 macrophages.
  • Figure 5 is graph showing the results of a screening assay for assessing the effect of mitoxantrone on proliferation of human fibroblasts.
  • Figure 6 is graph showing the results of a screening assay for assessing the effect of rapamycin on proliferation of human fibroblasts.
  • Figure 7 is graph showing the results of a screening assay for assessing the effect of paclitaxel on proliferation of human fibroblasts.
  • Figure 8 is a picture that shows an uninjured carotid artery from a rat balloon injury model.
  • Figure 9 is a picture that shows an injured carotid artery from a rat balloon injury model.
  • Figure 10 is a picture that shows a paclitaxel/mesh treated carotid artery in a rat balloon injury model.
  • Figure 11 A schematically depicts the transcriptional regulation of matrix metalloproteinases.
  • Figure 11 B is a blot which demonstrates that IL-1 stimulates AP-1 transcriptional activity.
  • Figure 11 C is a graph which shows that IL-1 induced binding activity decreased in lysates from chondrocytes which were pretreated with paclitaxel.
  • Figure 11 D is a blot which shows that IL-1 induction increases collagenase and stromelysin in RNA levels in chondrocytes, and that this induction can be inhibited by pretreatment with paclitaxel.
  • Figures 12A-H are blots that show the effect of various anti- microtubule agents in inhibiting collagenase expression.
  • Figure 13 is a graph showing the results of a screening assay for assessing the effect of paclitaxel on smooth muscle cell migration.
  • Figure 14 is a graph showing the results of a screening assay for assessing the effect of geldanamycin on IL-1 ⁇ production by THP-1 macrophages.
  • Figure 15 is a graph showing the results of a screening assay for assessing the effect of geldanamycin on IL-8 production by THP-1 macrophages.
  • Figure 16 is a graph showing the results of a screening assay for assessing the effect of geldanamycin on MCP-1 production by THP-1 macrophages.
  • Figure 17 is graph showing the results of a screening assay for assessing the effect of paclitaxel on proliferation of smooth muscle cells.
  • Figure 18 is graph showing the results of a screening assay for assessing the effect of paclitaxel for proliferation of the murine RAW 264.7 macrophage cell line.
  • Figure 19 is a bar graph showing the area of granulation tissue in carotid arteries exposed to silk coated perivascular polyurethane (PU) films relative to arteries exposed to uncoated PU films.
  • Figure 20 is a bar graph showing the area of granulation tissue in carotid arteries exposed to silk suture coated perivascular PU films relative to arteries exposed to uncoated PU films.
  • PU perivascular polyurethane
  • Figure 21 is a bar graph showing the area of granulation tissue in carotid arteries exposed to natural and purified silk powder and wrapped with perivascular PU film relative to a control group in which arteries are wrapped with perivascular PU film only.
  • Figure 22 is a bar graph showing the area of granulation tissue (at
  • Medical device “implant”, “medical device or implant”, “implant/device”, “the device”, and the like are used synonymously to refer to any object that is designed to be placed partially or wholly within a patient's body for one or more therapeutic or prophylactic purposes such as for restoring physiological function, alleviating symptoms associated with disease, delivering therapeutic agents, and/or repairing or replacing or augmenting etc. damaged or diseased organs and tissues.
  • While medical devices are normally composed of biologically compatible synthetic materials (e.g., medical-grade stainless steel, titanium and other metals; exogenous polymers, such as polyurethane, silicon, PLA, PLGA), other materials may also be used in the construction of the medical device or implant.
  • Specific medical devices and implants that are particularly useful for the practice of this invention include devices and implants that are used to provide electrical stimulation to the central and peripheral nervous system (including the autonomic system), cardiac muscle tissue (including myocardial conduction pathways), smooth muscle tissue and skeletal muscle tissue.
  • Electrical device refers to a medical device having electrical components that can be placed in contact with tissue in an animal host and can provide electrical excitation to nervous or muscular tissue.
  • Electrical devices can generate electrical impulses and may be used to treat many bodily dysfunctions and disorders by blocking, masking, or stimulating electrical signals within the body.
  • Electrical medical devices of particular utility in the present invention include, but are not restricted to, devices used in the treatment of cardiac rhythm abnormalities, pain relief, epilepsy, Parkinson's Disease, movement disorders, obesity, depression, anxiety and hearing loss.
  • Neurostimulator or “Neurostimulation Device” refers to an electrical device for electrical excitation of the central, autonomic, or peripheral nervous system.
  • the neurostimulator sends electrical impulses to an organ or tissue.
  • the neurostimulator may include electrical leads as part of the electrical stimulation system.
  • Neurostimulation may be used to block, mask, or stimulate electrical signals in the body to treat dysfunctions, including, without limitation, pain, seizures, anxiety disorders, depression, ulcers, deep vein thrombosis, muscular atrophy, obesity, joint stiffness, muscle spasms, osteoporosis, scoliosis, spinal disc degeneration, spinal cord injury, deafness, urinary dysfunction and gastroparesis.
  • Neurostimulation may be delivered to many different parts of the nervous system, including, spinal cord, brain, vagus nerve, sacral nerve, gastric nerve, auditory nerves, as well as organs, bone, muscles and tissues. As such, neurostimulators are developed to conform to the different anatomical structures and nervous system characteristics.
  • Cardiac Stimulation Device or “Cardiac Rhythm Management Device” or “Cardiac Pacemaker” or “Implantable Cardiac Defibrillator (ICD)” all refer to an electrical device for electrical excitation of cardiac muscle tissue (including the specialized cardiac muscle cells that make up the conductive pathways of the heart).
  • the cardiac pacemaker sends electrical impulses to the muscle (myocardium) or conduction tissue of the heart.
  • the pacemaker may include electrical leads as part of the electrical stimulation system.
  • Cardiac pacemakers may be used to block, mask, or stimulate electrical signals in the heart to treat dysfunctions, including, without limitation, atrial rhythm abnormalities, conduction abnormalities and ventricular rhythm abnormalities.
  • Electrical lead refers to an electrical device that is used as a conductor to carry electrical signals from the generator to the tissues.
  • electrical leads are composed of a connector assembly, a lead body (i.e., conductor) and an electrode.
  • the electrical lead may be a wire or other material that transmits electrical impulses from a generator (e.g., pacemaker, defibrillator, or other neurostimulator).
  • Electrical leads may be unipolar, in which they are adapted to provide effective therapy with only one electrode. Multi-polar leads are also available, including bipolar, tripolar and quadripolar leads.
  • Fibrosis or “Scarring” refers to the formation of fibrous (scar) tissue (or in the case of injury in the CNS - the formation of glial tissue, or “gliosis", by astrocytes) in response to injury or medical intervention.
  • Therapeutic agents which inhibit fibrosis or scarring can do so through one or more mechanisms including: inhibiting angiogenesis, inhibiting migration or proliferation of connective tissue cells (such as fibroblasts, smooth muscle cells, vascular smooth muscle cells), reducing ECM production, and/or inhibiting tissue remodeling.
  • Therapeutic agents which inhibit gliosis can do so through one or more mechanisms including: inhibiting migration of glial cells, inhibition of hypertrophy of glial cells, and/or inhibiting proliferation of glial cells.
  • inhibitors described in this invention may have the additional benefit of also reducing tissue regeneration (the replacement of injured cells by cells of the same type) when appropriate.
  • “Inhibit fibrosis”, “reduce fibrosis”, “inhibit gliosis”, “reduce gliosis” and the like are used synonymously to refer to the action of agents or compositions which result in a statistically significant decrease in the formation of fibrous or glial tissue that may be expected to occur in the absence of the agent or composition.
  • Inhibitor refers to an agent which prevents a biological process from occurring or slows the rate or degree of occurrence of a biological process.
  • the process may be a general one such as scarring or refer to a specific biological action such as, for example, a molecular process resulting in release of a cytokine.
  • Antagonist refers to an agent which prevents a biological process from occurring or slows the rate or degree of occurrence of a biological process. While the process may be a general one, typically this refers to a drug mechanism where the drug competes with a molecule for an active molecular site or prevents a molecule from interacting with the molecular site. In these situations, the effect is that the molecular process is inhibited.
  • Ant refers to an agent which stimulates a biological process or rate or degree of occurrence of a biological process.
  • the process may be a general one such as scarring or refer to a specific biological action such as, for example, a molecular process resulting in release of a cytokine.
  • Anti-microtubule agents should be understood to include any protein, peptide, chemical, or other molecule which impairs the function of microtubules, for example, through the prevention or stabilization of polymerization. Compounds that stabilize polymerization of microtubules are referred to herein as "microtubule stabilizing agents.” A wide variety of methods may be utilized to determine the anti-microtubule activity of a particular compound, including for example, assays described by Smith et al. (Cancer Lett.
  • Release of an agent refers to a statistically significant presence of the agent, or a subcomponent thereof, which has disassociated from the implant/device and/or remains active on the surface of (or within) the device/implant.
  • Biodegradable refers to materials for which the degradation process is at least partially mediated by, and/or performed in, a biological system.
  • Degradation refers to a chain scission process by which a polymer chain is cleaved into oligomers and monomers. Chain scission may occur through various mechanisms, including, for example, by chemical reaction (e.g., hydrolysis) or by a thermal or photolytic process.
  • Polymer degradation may be characterized, for example, using gel permeation chromatography (GPC), which monitors the polymer molecular mass changes during erosion and drug release.
  • GPC gel permeation chromatography
  • Biodegradable also refers to materials may be degraded by an erosion process mediated by, and/or performed in, a biological system.
  • Erosion refers to a process in which material is lost from the bulk.
  • the material may be a monomer, an oligomer, a part of a polymer backbone, or a part of the polymer bulk.
  • Erosion includes (i) surface erosion, in which erosion affects only the surface and not the inner parts of a matrix; and (ii) bulk erosion, in which the entire system is rapidly hydrated and polymer chains are cleaved throughout the matrix.
  • erosion generally occurs by one of three basic mechanisms (see, e.g., Heller, J., CRC Critical Review in Therapeutic Drug Carrier Systems (1984), 1 (1 ), 39- 90); Siepmann, J. et al., Adv. Drug Del. Rev.
  • analogue refers to a chemical compound that is structurally similar to a parent compound, but differs slightly in composition (e.g., one atom or functional group is different, added, or removed).
  • the analogue may or may not have different chemical or physical properties than the original compound and may or may not have improved biological and/or chemical activity.
  • the analogue may be more hydrophilic or it may have altered reactivity as compared to the parent compound.
  • the analogue may mimic the chemical and/or biologically activity of the parent compound (i.e., it may have similar or identical activity), or, in some cases, may have increased or decreased activity.
  • the analogue may be a naturally or non- naturally occurring (e.g., recombinant) variant of the original compound.
  • An example of an analogue is a mutein (i.e., a protein analogue in which at least one amino acid is deleted, added, or substituted with another amino acid).
  • analogues include isomers (enantiomers, diasteromers, and the like) and other types of chiral variants of a compound, as well as structural isomers.
  • the analogue may be a branched or cyclic variant of a linear compound.
  • a linear compound may have an analogue that is branched or otherwise substituted to impart certain desirable properties (e.g., improve hydrophilicity or bioavailability).
  • derivative refers to a chemically or biologically modified version of a chemical compound that is structurally similar to a parent compound and (actually or theoretically) derivable from that parent compound.
  • a “derivative” differs from an “analogue” in that a parent compound may be the starting material to generate a "derivative,” whereas the parent compound may not necessarily be used as the starting material to generate an “analogue.”
  • a derivative may or may not have different chemical or physical properties of the parent compound. For example, the derivative may be more hydrophilic or it may have altered reactivity as compared to the parent compound.
  • Derivatization may involve substitution of one or more moieties within the molecule (e.g., a change in functional group).
  • a hydrogen may be substituted with a halogen, such as fluorine or chlorine, or a hydroxyl group (-OH) may be replaced with a carboxylic acid moiety (-COOH).
  • derivative also includes conjugates, and prodrugs of a parent compound (i.e., chemically modified derivatives which can be converted into the original compound under physiological conditions).
  • the prodrug may be an inactive form of an active agent. Under physiological conditions, the prodrug may be converted into the active form of the compound.
  • Prodrugs may be formed, for example, by replacing one or two hydrogen atoms on nitrogen atoms by an acyl group (acyl prodrugs) or a carbamate group (carbamate prodrugs). More detailed information relating to prodrugs is found, for example, in Fleisher et al., Advanced Drug Delivery Reviews 19 (1996) 115; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; or H. Bundgaard, Drugs of the Future 16 (1991 ) 443.
  • the term "derivative" is also used to describe all solvates, for example hydrates or adducts (e.g., adducts with alcohols), active metabolites, and salts of the parent compound.
  • acidic groups for example carboxylic acid groups
  • alkali metal salts or alkaline earth metal salts e.g., sodium salts, potassium salts, magnesium salts and calcium salts
  • physiologically tolerable quaternary ammonium ions and acid addition salts with ammonia and physiologically tolerable organic amines such as, for example, triethylamine, ethanolamine or tris-(2-hydroxyethyl)amine.
  • Basic groups can form acid addition salts, for example with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic acids and sulfonic acids such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid.
  • Compounds which simultaneously contain a basic group and an acidic group for example a carboxyl group in addition to basic nitrogen atoms, can be present as zwitterions.
  • Salts can be obtained by customary methods known to those skilled in the art, for example by combining a compound with an inorganic or organic acid or base in a solvent or diluent, or from other salts by cation exchange or anion exchange.
  • concentration ranges, percentage range, or ratio range recited herein are to be understood to include concentrations, percentages or ratios of any integer within that range and fractions thereof, such as one tenth and one hundredth of an integer, unless otherwise indicated.
  • any number range recited herein relating to any physical feature, such as polymer subunits, size or thickness are to be understood to include any integer within the recited range, unless otherwise indicated.
  • compositions, methods and devices relating to medical devices and implants which greatly increase their ability to inhibit the formation of reactive scar (or glial) tissue on, or around, the surface of the device or implant. Described in more detail below are methods for constructing medical devices or implants, compositions and methods for generating medical devices and implants which inhibit fibrosis, and methods for utilizing such medical devices and implants.
  • Medical devices having electrical components can be implanted in the body to provide electrical conduction to the central and peripheral nervous system (including the autonomic system), cardiac muscle tissue (including myocardial conduction pathways), smooth muscle tissue and skeletal muscle tissue. These electrical impulses are used to treat many bodily dysfunctions and disorders by blocking, masking, stimulating, or replacing electrical signals within the body.
  • Examples include pacemaker leads used to maintain the normal rhythmic beating of the heart; defibrillator leads used to "re-start” the heart when it stops beating; peripheral nerve stimulating devices to treat chronic pain; deep brain electrical stimulation to treat conditions such as tremor, Parkinson's disease, movement disorders, epilepsy, depression and psychiatric disorders; and vagal nerve stimulation to treat epilepsy, depression, anxiety, obesity, migraine and Alzheimer's Disease.
  • the clinical function of an electrical device such as a cardiac pacemaker lead, neurostimulation lead, or other electrical lead depends upon the device being able to effectively maintain intimate anatomical contact with the target tissue (typically electrically excitable cells such as muscle or nerve) such that electrical conduction from the device to the tissue can occur.
  • fibrous encapsulation of the device can occur even after a successful implantation if the device is manipulated (some patients continuously "fiddle" with a subcutaneous implant) or irritated by the daily activities of the patient.
  • the electrical characteristics of the electrode-tissue interface degrade, and the device may fail to function properly. For example, it may require additional electrical current from the lead to overcome the extra resistance imposed by the intervening scar (or glial) tissue. This can shorten the battery life of an implant (making more frequent removal and re-implantation necessary), prevent electrical conduction altogether (rendering the implant clinically ineffective) and/or cause damage to the target tissue.
  • the surrounding tissue may be inadvertently damaged from the inflammatory foreign body response, which can result in loss of function or tissue necrosis.
  • the present invention addresses these problems. Exemplary electrical devices are described next.
  • the electrical device may be a neurostimulation device where a pulse generator delivers an electrical impulse to a nervous tissue (e.g., CNS, peripheral nerves, autonomic nerves) in order to regulate its activity.
  • a nervous tissue e.g., CNS, peripheral nerves, autonomic nerves
  • a fibrotic reaction may adversely affect the functioning of the device or the biological problem for which the device was implanted or used.
  • fibrotic encapsulation of the electrical lead or the growth of fibrous tissue between the lead and the target nerve tissue slows, impairs, or interrupts electrical transmission of the impulse from the device to the tissue.
  • Neurostimulation devices are used as alternative or adjunctive therapy for chronic, neurodegenerative diseases, which are typically treated with drug therapy, invasive therapy, or behavioral/lifestyle changes. Neurostimulation may be used to block, mask, or stimulate electrical signals in the body to treat dysfunctions, including, without limitation, pain, seizures, anxiety disorders, depression, ulcers, deep vein thrombosis, muscular atrophy, obesity, joint stiffness, muscle spasms, osteoporosis, scoliosis, spinal disc degeneration, spinal cord injury, deafness, urinary dysfunction and gastroparesis.
  • dysfunctions including, without limitation, pain, seizures, anxiety disorders, depression, ulcers, deep vein thrombosis, muscular atrophy, obesity, joint stiffness, muscle spasms, osteoporosis, scoliosis, spinal disc degeneration, spinal cord injury, deafness, urinary dysfunction and gastroparesis.
  • Neurostimulation may be delivered to many different parts of the nervous system, including, spinal cord, brain, vagus nerve, sacral nerve, gastric nerve, auditory nerves, as well as organs, bone, muscles and tissues.
  • neurostimulators are developed to conform to the different anatomical structures and nervous system characteristics.
  • Representative examples of neurologic and neurosurgical implants and devices that can be coated with, or otherwise constructed to contain and/or release the therapeutic agents provided herein, include, e.g., nerve stimulator devices to provide pain relief, devices for continuous subarachnoid infusions, implantable electrodes, stimulation electrodes, implantable pulse generators, electrical leads, stimulation catheter leads, neurostimulation systems, electrical stimulators, cochlear implants, auditory stimulators and microstimulators.
  • Neurostimulation devices may also be classified based on their source of power, which includes: battery powered, radio-frequency (RF) powered, or a combination of both types.
  • battery powered neurostimulators an implanted, non-rechargeable battery is used for power.
  • the battery and leads are all surgically implanted and thus the neurostimulation device is completely internal.
  • the settings of the totally implanted neurostimulator are controlled by the patient through an external magnet.
  • the lifetime of the implant is generally limited by the duration of battery life and ranges from two to four years depending upon usage and power requirements.
  • RF-powered neurostimulation devices the radio-frequency is transmitted from an externally worn source to an implanted passive receiver.
  • the radio-frequency system enables greater power resources and thus, multiple leads may be used in these systems.
  • Specific examples include a neurostimulator that has a battery power source contained within to supply power over an eight hour period in which power may be replenished by an external radio frequency coupled device (See e.g., U.S. Patent No. 5,807,397) or a microstimulator which is controlled by an external transmitter using data signals and powered by radio frequency (See e.g., U.S. Patent No. 6,061 ,596).
  • Examples of commercially available neurostimulation products include a radio-frequency powered neurostimulator comprised of the 3272 MATTRIX Receiver, 3210 MATTRIX Transmitter and 3487A PISCES-QUAD Quadripolar Leads made by Medtronic, Inc. (Minneapolis, MN). Medtronic also sells a battery-powered ITREL 3 Neurostimulator and SYNERGY Neurostimulator, the INTERSIM Therapy for sacral nerve stimulation for urinary control, and leads such as the 3998 SPECIFY Lead and 3587A RESUME II Lead.
  • a radio-frequency powered neurostimulator comprised of the 3272 MATTRIX Receiver, 3210 MATTRIX Transmitter and 3487A PISCES-QUAD Quadripolar Leads made by Medtronic, Inc. (Minneapolis, MN). Medtronic also sells a battery-powered ITREL 3 Neurostimulator and SYNERGY Neurostimulator, the INTERSIM Therapy for sacral nerve stimulation for urinary control
  • a neurostimulation device is a gastric pacemaker, in which multiple electrodes are positioned along the Gl tract to deliver a phased electrical stimulation to pace peristaltic movement of the material through the Gl tract. See, e.g., U.S. Patent No. 5,690,691.
  • a representative example of a gastric stimulation device is the ENTERRA Gastric Electrical Stimulation (GES) from Medtronic, Inc. (Minneapolis, MN).
  • the neurostimulation device, particularly the lead(s) must be positioned in a very precise manner to ensure that stimulation is delivered to the correct anatomical location in the nervous system.
  • a neurostimulation device can migrate following surgery, or excessive scar (or glial) tissue growth can occur around the implant, which can lead to a reduction in the performance of these devices (as described previously).
  • Neurostimulator devices that release a therapeutic agent for reducing scarring (or gliosis) at the electrode-tissue interface can be used to increase the efficacy and/or the duration of activity (particularly for fully-implanted, battery-powered devices) of the implant.
  • the present invention provides neurostimulator leads that are coated with an anti-scarring agent or a composition that includes an anti-scarring (or anti-gliosis) agent.
  • Neurostimulation for the Treatment of Chronic Pain is one of the most important clinical problems in all of medicine. For example, it is estimated that over 5 million people in the United States are disabled by back pain. The economic cost of chronic back pain is enormous, resulting in over 100 million lost work days annually at an estimated cost of $50-100 billion. It has been reported that approximately 40 million Americans are afflicted with recurrent headaches and that the cost of medications for this condition exceeds $4 billion a year. A further 8 million people in the U.S. report that they experience chronic neck or facial pain and spend an estimated $2 billion a year for treatment. The cost of managing pain for oncology patients is thought to approach $12 billion.
  • Chronic pain disables more people than cancer or heart disease and costs the American public more than both cancer and heart disease combined. In addition to the physical consequences, chronic pain has numerous other costs including loss of employment, marital discord, depression and prescription drug addiction. It goes without saying, therefore, that reducing the morbidity and costs associated with persistent pain remains a significant challenge for the healthcare system. Intractable severe pain resulting from injury, illness, scoliosis, spinal disc degeneration, spinal cord injury, malignancy, arachnoiditis, chronic disease, pain syndromes (e.g., failed back syndrome, complex regional pain syndrome) and other causes is a debilitating and common medical problem.
  • pain syndromes e.g., failed back syndrome, complex regional pain syndrome
  • neurostimulation devices have been developed to treat severe intractable pain that is resistant to other traditional treatment modalities such as drug therapy, invasive therapy (surgery), or behavioral/lifestyle changes.
  • neurostimulation works by delivering low voltage electrical stimulation to the spinal cord or a particular peripheral nerve in order to block the sensation of pain.
  • Pain management neurostimulation systems consist of a power source that generates the electrical stimulation, leads (typically 1 or 2) that deliver electrical stimulation to the spinal cord or targeted peripheral nerve, and an electrical connection that connects the power source to the leads.
  • Neurostimulation systems can be battery powered, radio-frequency powered, or a combination of both.
  • neurostimulation devices those that are surgically implanted and are completely internal (i.e., the battery and leads are implanted), and those with internal (leads and radio- frequency receiver) and external (power source and antenna) components.
  • an implanted, non-rechargeable battery and the leads are all surgically implanted.
  • the settings of the totally implanted neurostimulator may be controlled by the host by using an external magnet and the implant has a lifespan of two to four years.
  • the radio-frequency is transmitted from an externally worn source to an implanted passive receiver.
  • the radio-frequency system enables greater power resources and thus, multiple leads may be used.
  • neurostimulation devices that can be used for spinal cord stimulation in the management of pain control, postural positioning and other disorders. Examples of specific neurostimulation devices include those composed of a sensor that detects the position of the spine and a stimulator that automatically emits a series of pulses which decrease in amplitude when back is in a supine position. See e.g., U.S. Patent Nos.
  • the neurostimulator may be composed of electrodes and a control circuit which generates pulses and rest periods based on intervals corresponding to the body's activity and regeneration period as a treatment for pain. See e.g., U.S. Patent No. 5,354,320.
  • the neurostimulator which may be implanted within the epidural space parallel to the axis of the spinal cord, may transmit data to a receiver which generates a spinal cord stimulation pulse that may be delivered via a coupled, multi-electrode. See e.g., Patent No. 6,609,031.
  • the neurostimulator may be a stimulation catheter lead with a sheath and at least three electrodes that provide stimulation to neural tissue.
  • the neurostimulator may be a self- centering epidual spinal cord lead with a pivoting region to stabilize the lead which inflates when injected with a hardening agent. See e.g., U.S. Patent No. 6,308,103.
  • Other neurostimulators used to induce electrical activity in the spinal cord are described in, e.g., U.S. Patent Nos. 6,546,293; 6,236,892; 4,044,774 and 3,724,467.
  • Commercially available neurostimulation devices for the management of chronic pain include the SYNERGY, INTREL, X-TREL and MATTRIX neurostimulation systems from Medtronic, Inc.
  • the percutaneous leads in this system can be quadripolar (4 electrodes), such as the PISCES- QUAD, PISCES-QUAD PLUS and the PISCES-QUAD Compact, or octapolar (8 electrodes) such as the OCTAD lead.
  • the surgical leads themselves are quadripolar, such as the SPECIFY Lead, the RESUME II Lead, the RESUME TL Lead and the ON-POINT PNS Lead, to create multiple stimulation combinations and a broad area of paresthesia.
  • the device includes spinal cord stimulating devices and/or leads that are coated with an anti- scarring (or anti-gliosis) agent or a composition that includes an anti-scarring (or anti-gliosis) agent.
  • a composition that includes an anti-scarring agent can be infiltrated into the epidural space where the lead will be implanted.
  • Other commercially available systems that may useful for the practice of this invention as described above include the rechargeable PRECISION Spinal Cord Stimulation System (Advanced Bionics Corporation, Sylmar, CA; which is a Boston Scientific Company) which can drive up to 16 electrodes (see e.g., U.S. Patent No. 6,735,474; 6,735,475; 6,659,968; 6,622,048; 6,516,227 and 6,052,624).
  • the GENESIS XP Spinal Cord Stimulator available from Advanced Neuromodulation Systems, Inc. (Piano, TX; see e.g., U.S. Patent Nos.
  • VNS Vagus Nerve Stimulation
  • the leads may also benefit from the application of anti-fibrosis (or anti-gliosis) agents as described in this invention.
  • the leads must be accurately positioned adjacent to the portion of the spinal cord or the targeted peripheral nerve that is to be electrically stimulated.
  • Neurostimulators can migrate following surgery or excessive tissue growth or extracellular matrix deposition can occur around neurostimulators, which can lead to a reduction in the functioning of these devices.
  • Neurostimulator devices that release therapeutic agent for reducing scarring at the electrode-tissue interface can be used to increase the duration that these devices clinically function.
  • the device includes neurostimulator devices and/or leads that are coated with an anti-scarring (or anti-gliosis) agent or a composition that includes an anti-scarring (or anti- gliosis) agent.
  • a composition that includes an anti-scarring (anti-gliosis) agent can be infiltrated into the tissue surrounding the implanted portion (particularly the leads) of the pain management neurostimulation device.
  • Neurostimulation for the Treatment of Parkinson's Disease Neurostimulation devices implanted into the brain are used to control the symptoms associated with Parkinson's disease or essential tremor. Typically, these are dual chambered stimulator devices (similar to cardiac pacemakers) that deliver bilateral stimulation to parts of the brain that control motor function.
  • Electrodes are implanted in the brain (usually bilaterally in the subthalamic nucleus or the globus pallidus interna) for the treatment of levodopa-responsive Parkinson's and one is implanted (in the ventral intermediate nucleus of the thalamus) for the treatment of tremor.
  • the electrodes are implanted in the brain by a functional stereotactic neurosurgeon using a stereotactic head frame and MRI or CT guidance.
  • the electrodes are connected via extensions (which run under the skin of the scalp and neck) to a neurostimulatory (pulse generating) device implanted under the skin near the clavicle.
  • a neurologist can then optimize symptom control by adjusting stimulation parameters using a noninvasive control device that communicates with the neurostimulator via telemetry.
  • the patient is also able to turn the system on and off using a magnet and control the device (within limits set by the neurologist) settings using a controller device.
  • This form of deep brain stimulation has also been investigated for the treatment pain, epilepsy, psychiatric conditions (obsessive-compulsive disorder) and dystonia.
  • the neurostimulator may be an intracranially implanted electrical control module and a plurality of electrodes which stimulate the brain tissue with an electrical signal at a defined frequency. See e.g., U.S. Patent No. 6,591 ,138.
  • the neurostimulator may be a system composed of at least two electrodes adapted to the cranium and a control module adapted to be implanted beneath the scalp for transmitting output electrical signals and also external equipment for providing two-way communication. See e.g., U.S. Patent No. 6,016,449.
  • the neurostimulator may be an implantable assembly composed of a sensor and two electrodes, which are used to modify the electrical activity in the brain. See e.g., U.S. Patent No. 6,466,822.
  • a commercial example of a device used to treat Parkinson's disease and essential tremor includes the ACTIVA System by Medtronic, Inc. (see, for example, U.S. Patent Nos., 6,671 ,544 and 6,654,642).
  • This system consists of the KINETRA Dual Chamber neurostimulator, the SOLETRA neurostimulator or the INTREL neurostimulator, connected to an extension (an insulated wire), that is further connected to a DBS lead.
  • the DBS lead consists of four thin, insulated, coiled wires bundled with polyurethane. Each of the four wires ends in a 1.5 mm long electrode.
  • all or parts of the DBS lead may be suitable for coating with a fibrosis/gliosis-inhibiting composition, a preferred embodiment involves delivering the therapeutic agent from the surface of the four electrodes.
  • a composition that includes an anti-gliosis agent can be infiltrated into the brain tissue surrounding the leads.
  • Vagal Nerve Stimulation for the Treatment of Epilepsy Neurostimulation devices are also used for vagal nerve stimulation in the management of pharmacoresistant epilepsy (i.e., epilepsy that is uncontrolled despite appropriate medical treatment with ant-epileptic drugs). Approximately 30% of epileptic patients continue to have seizures despite of multiple attempts at controlling the disease with drug therapy or are unable to tolerate the side effects of their medications. It is estimated that approximately 2.5 million patients in the United States suffer from treatment-resistant epilepsy and may benefit from vagal nerve stimulation therapy. As such, inadequate seizure control remains a significant medical problem with many patients suffering from diminished self esteem, poor academic achievement and a restricted lifestyle as a result of their illness.
  • the vagus nerve also called the 10 th cranial nerve contains primarily afferent sensory fibres that carry information from the neck, thorax and abdomen to the nucleus tractus soltarius of the brainstem and on to multiple noradrenergic and serotonergic neuromodulatory systems in the brain and spinal cord.
  • Vagal nerve stimulation has been shown to induce progressive EEG changes, alter bilateral cerebral blood flow, and change blood flow to the thalamus.
  • VNS has been demonstrated clinically to terminate seizures after seizure onset, reduce the severity and frequency of seizures, prevent seizures when used prophylactically over time, improve quality of life, and reduce the dosage, number and side effects of anti-epileptic medications (resulting in improved alertness, mood, memory).
  • a bipolar electrical lead is surgically implanted such that it transmits electrical stimulation from the pulse generator to the left vagus nerve in the neck.
  • the pulse generator is an implanted, lithium carbon monofluoride battery-powered device that delivers a precise pattern of stimulation to the vagus nerve.
  • the pulse generator can be programmed (using a programming wand) by the neurologist to suit an individual patient's symptoms, while the patient can turn the device on and off through the use of an external magnet.
  • Chronic electrical stimulation which can be used as a direct treatment for epilepsy is described in, for example, U.S. Patent No. 6,016,449, whereby, an implantable neurostimulator is coupled to relatively permanent deep brain electrodes.
  • the implantable neurostimulator may be composed of an implantable electrical lead having a furcated, or split, distal portion with two or more separate end segments, each of which bears at least one sensing or stimulation electrode, which may be used to treat epilepsy and other neurological disorders. See e.g., U.S. Patent No. 6,597,953.
  • VNS system A commercial example of a VNS system is the product produced by Cyberonics, Inc. that includes the Model 300 and Model 302 leads, the Model 101 and Model 102R pulse generators, the Model 201 programming wand and Model 250 programming software, and the Model 220 magnets.
  • These products manufactured by Cyberonics, Inc. may be described, for example, in U.S. Patent Nos. 5,540,730 and 5,299,569.
  • the leads must be accurately positioned adjacent to the left vagus nerve. If excessive scar tissue growth or extracellular matrix deposition occurs around the VNS leads, this can reduce the efficacy of the device.
  • VNS devices that release a therapeutic agent able to reducing scarring at the electrode-tissue interface can increase the efficiency of impulse transmission and increase the duration that these devices function clinically.
  • the device includes VNS devices and/or leads that are coated with an anti-scarring agent or a composition that includes an anti-scarring agent.
  • a composition that includes an anti- scarring agent can be infiltrated into the tissue surrounding the vagus nerve where the lead will be implanted.
  • Vagal Nerve Stimulation for the Treatment of Other Disorders It was discovered during the use of VNS for the treatment of epilepsy that some patients experienced an improvement in their mood during therapy.
  • VNS is currently being examined for use in the management of treatment-resistant mood disorders such as depression and anxiety.
  • Depression remains an enormous clinical problem in the Western World with over 1 % (25 million people in the United States) suffering from depression that is inadequately treated by pharmacotherapy.
  • Vagal nerve stimulation has been examined in the management of conditions such as anxiety (panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder), obesity, migraine, sleep disorders, dementia, Alzheimer's disease and other chronic or degenerative neurological disorders.
  • VNS has also been examined for use in the treatment of medically significant obesity.
  • the implantable neurostimulator for the treatment of neurologipal disorders may be composed of an implantable electrical lead having a furcated, or split, distal portion with two or more separate end segments, each of which bears at least one sensing or stimulation electrode. See e.g., U.S. Patent No. 6,597,953.
  • the implantable neurostimulator may be an apparatus for treating Alzheimer's disease and dementia, particularly for neuro modulating or stimulating left vagus nerve, composed of an implantable lead-receiver, external stimulator, and primary coil. See e.g., U.S. Patent No. 6,615,085. Cyberonics, Inc.
  • VNS system manufactures the commercially available VNS system, including the Model 300 and Model 302 leads, the Model 101 and Model 102R pulse generators, the Model 201 programming wand and Model 250 programming software, and the Model 220 magnets.
  • These products as well as others that are being developed by Cyberonics, Inc. may be used to treat neurological disorders, including depression (see e.g., U.S. Patent No. 5,299,569), dementia (see e.g., U.S. Patent No. 5,269,303), migraines (see e.g., U.S. Patent No. 5,215,086), sleep disorders (see e.g., U.S. Patent No. 5,335,657) and obesity (see e.g., U.S. Patent Nos.
  • VNS devices that release a therapeutic agent able to reducing scarring at the electrode-tissue interface can increase the efficiency of impulse transmission and increase the duration that these devices function clinically for the treatment of depression, anxiety, obesity, sleep disorders and dementia.
  • the device includes VNS devices and/or leads that are coated with an anti- scarring agent or a composition that includes an anti-scarring agent.
  • a composition that includes an anti- scarring agent can be infiltrated into the tissue surrounding the vagus nerve where the lead will be implanted.
  • Sacral Nerve Stimulation for Bladder Control Problems Sacral nerve stimulation is used in the management of patients with urinary control problems such as urge incontinence, nonobstructive urinary retention, or urgency-frequency. Millions of people suffer from bladder control problems and a significant percentage (estimated to be in excess of 60%) is not adequately treated by other available therapies such as medications, absorbent pads, external collection devices, bladder augmentation or surgical correction.
  • Mild electrical stimulation of the sacral nerve is used to influence the functioning of the bladder, urinary sphincter, and the pelvic floor muscles (all structures which receive nerve supply from the sacral nerve).
  • An electrical lead is surgically implanted adjacent to the sacral nerve and a neurostimulator is implanted subcutaneously in the upper buttock or abdomen; the two are connected by an extension.
  • the use of tined leads allows sutureless anchoring of the leads and minimally-invasive placement of the leads under local anesthesia.
  • a handheld programmer is available for adjustment of the device by the attending physician and a patient-controlled programmer is available to adjust the settings and to turn the device on and off.
  • the pulses are adjusted to provide bladder control and relieve the patient's symptoms.
  • Several neurostimulation systems have been described for sacral nerve stimulation in which electrical stimulation is targeted towards the bladder, pelvic floor muscles, bowel and/or sexual organs.
  • the neurostimulator may be an electrical stimulation system composed of an electrical stimulator and leads having insulator sheaths, which may be anchored in the sacrum using minimally-invasive surgery. See e.g., U.S. Patent No. 5,957,965.
  • the neurostimulator may be used to condition pelvic, sphincter or bladder muscle tissue.
  • the neurostimulator may be intramuscular electrical stimulator composed of a pulse generator and an elongated medical lead that is used for electrically stimulating or sensing electrical signals originating from muscle tissue.
  • a neurostimulation system consists of a leadless, tubular-shaped microstimulator that is implanted at pelvic floor muscles or associated nerve tissue that need to be stimulated to treat urinary incontinence. See e.g., U.S. Patent No. 6,061 ,596.
  • a commercially available example of a neurostimulation system to treat bladder conditions is the INTERSTIM Sacral Nerve Stimulation System made by Medtronic, Inc. See e.g., U.S.
  • the leads must be accurately positioned adjacent to the sacral nerve, bladder, sphincter or pelvic muscle (depending upon the particular system employed). If excessive scar tissue growth or extracellular matrix deposition occurs around the leads, efficacy can be compromised. Sacral nerve stimulating devices (such as INTERSTIM) that release a therapeutic agent able to reducing scarring at the electrode-tissue interface can increase the efficiency of impulse transmission and increase the duration that these devices function clinically.
  • the device includes sacral nerve stimulating devices and/or leads that are coated with an anti-scarring agent or a composition that includes an anti-scarring agent.
  • a composition that includes an anti-scarring agent can be infiltrated into the tissue surrounding the sacral nerve where the lead will be implanted.
  • the device includes bladder or pelvic muscle stimulating devices, leads, and/or sensors that are coated with an anti-scarring agent or a composition that includes an anti-scarring agent.
  • a composition that includes an anti-scarring agent can be directly infiltrated into the muscle tissue itself (preferably adjacent to the lead and/or sensor that is delivering an impulse or monitoring the activity of the muscle).
  • Gastric Nerve Stimulation for the Treatment of Gl Disorders is used to influence gastric emptying and satiety sensation in the management of clinically significant obesity or problems associated with impaired Gl motility. Morbid obesity has reached epidemic proportions and is thought to affect over 25 million Americans and lead to significant health problems such as diabetes, heart attack, stroke and death. Mild electrical stimulation of the gastric nerve is used to influence the functioning of the upper Gl tract and stomach (all structures which receive nerve supply from the gastric nerve). An electrical lead is surgically implanted adjacent to the gastric nerve and a neurostimulator is implanted subcutaneously; the two are connected by an extension.
  • a handheld programmer is available for adjustment of the device by the attending physician and a patient-controlled programmer is available to adjust the settings and to turn the device on and off.
  • the pulses are adjusted to provide a sensation of satiety and relieve the sensation of hunger experienced by the patient. This can reduce the amount of food (and hence caloric) intake and allow the patient to lose weight successfully.
  • Related devices include neurostimulation devices used to stimulate gastric emptying in patients with impaired gastric motility, a neurostimulator to promote bowel evacuation in patients with constipation (stimulation is delivered to the colon), and devices targeted at the bowel for patients with other Gl motility disorders.
  • neurostimulation devices deliver impulses to the colon and rectum to manage constipation and are composed of electrical leads, electrodes and an implanted stimulation generator. See e.g., U.S. Patent No. 6,026,326.
  • the neurostimulator may be a pulse generator and electrodes that electrically stimulate the neuromuscular tissue of the viscera to treat obesity. See e.g., U.S. Patent No. 6,606,523.
  • the neurostimulator may be a hermetically sealed implantable pulse generator that is electrically coupled to the gastrointestinal tract and emits two rates of electrical stimulation to treat gastroparesis for patients with impaired gastric emptying. See e.g., U.S. Patent No. 6,091 ,992.
  • the neurostimulator may be composed of an electrical signal controller, connector wire and attachment lead which generates continuous low voltage electrical stimulation to the fundus of the stomach to control appetite. See e.g., U.S. Patent No. 6,564,101.
  • Other neurostimulators that are used to electrically stimulate the gastrointestinal tract are described in, e.g., U.S. Patent Nos. 6,453,199; 6,449,511 and 6,243,607.
  • IGS TRANSCEND Implantable Gastric Stimulator
  • Transneuronix, Inc. Mt. Arlington, NJ
  • the IGS is a programmable, bipolar pulse generator that delivers small bursts of electrical pulses through the lead to the stomach wall to treat obesity. See, e.g., U.S. Patent Nos. 6,684,104 and 6,165,084.
  • the leads must be accurately positioned adjacent to the gastric nerve. If excessive scar tissue growth or extracellular matrix deposition occurs around the leads, efficacy can be compromised.
  • Gastric nerve stimulating devices (and other implanted devices designed to influence Gl motility) that release a therapeutic agent able to reduce scarring at the electrode-tissue interface can increase the efficiency of impulse transmission and increase the duration that these devices function clinically.
  • the device includes gastric nerve stimulating devices and/or leads that are coated with an anti-scarring agent or a composition that includes an anti-scarring agent.
  • a composition that includes an anti-scarring agent can be infiltrated into the tissue surrounding the gastric nerve where the lead will be implanted.
  • Cochlear Implants for the Treatment of Deafness Neurostimulation is also used in the form of a cochlear implant that stimulates the auditory nerve for correcting sensorineural deafness.
  • a sound processor captures sound from the environment and processes it into a digital signal that is transmitted via an antenna through the skin to the cochlear implant.
  • the cochlear implant which is surgically implanted in the cochlea adjacent to the auditory nerve, converts the digital information into electrical signals that are communicated to the auditory nerve via an electrode array. Effectively, the cochlear implant serves to bypass the nonfunctional cochlear transducers and directly depolarize afferent auditory nerve fibers.
  • the treatment is used for adults with 70 dB or greater hearing loss (and able to understand up to 50% of words in a sentence using a hearing aid) or children 12 months or older with 90 dB hearing loss in both ears.
  • many implantations are performed without incident, approximately 12-15% of patients experience some complications. Histologic assessment of cochlear implants has revealed that several forms of injury and scarring can occur. Surgical trauma can induce cochlear fibrosis, cochlear neossification and injury to the membranous cochlea (including loss of the sensorineural elements).
  • a foreign body reaction along the implant and the electrode can produce a fibrous tissue response along the electrode array that has been associated with implant failure.
  • Coating the implant and/or the electrode with an anti-scarring composition may help reduce the incidence of failure.
  • fibrosis may be reduced or prevented by the infiltration of an anti-scarring agent into the tissue (the scala tympani) where the electrodes contact the auditory nerve fibers.
  • suitable cochlear implant systems or "bionic ears" have been described for use in association with this invention.
  • the neurostimulator may be composed of a plurality of transducer elements which detect vibrations and then generates a stimulus signal to a corresponding neuron connected to the cranial nerve.
  • the neurostimulator may be a cochlear implant having a sound-to-electrical stimulation encoder, a body implantable receiver-stimulator and electrodes, which emit pulses based on received electrical signals. See e.g., U.S. Patent No. 4,532,930.
  • the neurostimulator may be an intra-cochlear apparatus that is composed of a transducer that converts an audio signal into an electrical signal and an electrode array which electrically stimulates predetermined locations of the auditory nerve. See e.g., U.S. Patent No. 4,400,590.
  • the neurostimulator may be a stimulus generator for applying electrical stimuli to any branch of the 8 th nerve in a generally constant rate independent of audio modulation, such that it is perceived as active silence. See e.g., U.S. Patent No. 6,175,767.
  • the neurostimulator may be a subcranially implanted electromechanical system that has an input transducer and an output stimulator that converts a mechanical sound vibration into an electrical signal. See e.g., U.S. Patent No. 6,235,056.
  • the neurostimulator may be a cochlear implant that has a rechargeable battery housed within the implant for storing and providing electrical power. See e.g., U.S. Patent No. 6,067,474.
  • neurostimulators that are used as cochlear implants are described in, e.g., U.S. Patent Nos. 6,358,281 ; 6,308,101 and 5,603,726.
  • Several commercially available devices are available for the treatment of patients with significant sensorineural hearing loss and are suitable for use with the present invention.
  • the HIRESOLUTION Bionic Ear System (Boston Scientific Corp., Nattick, MA) consists of the HIRES AURIA Processor which processes sound and sends a digital signal to the HIRES 90K Implant that has been surgically implanted in the inner ear. See e.g., U.S. Patent Nos. 6,636,768; 6,309,410 and 6,259,951.
  • the electrode array that transmits the impulses generated by the HIRES 90K Implant to the nerve may benefit from an anti-scarring coating and/or the infiltration of an anti-scarring agent into the region around the electrode-nerve interface.
  • the PULSARci cochlear implant MED-EL GMBH, Innsbruck, Austria, see e.g., U.S. Patent Nos. 6,556,870 and 6,231 ,604
  • NUCLEUS 3 cochlear implant system Cochlear Corp., Lane Cove, Australia, see e.g., U.S. Patent Nos.
  • 6,807,445; 6,788,790; 6,554,762; 6,537,200 and 6,394,947) are other commercial examples of cochlear implants whose electrodes are suitable for coating with an anti-scarring composition (or infiltration of an anti-scarring agent into the region around the electrode-nerve interface) under the present invention.
  • the electrode arrays must be accurately positioned adjacent to the afferent auditory nerve fibers. If excessive scar tissue growth or extracellular matrix deposition occurs around the leads, efficacy can be compromised.
  • Cochlear implants that release a therapeutic agent able to reduce scarring at the electrode-tissue interface can increase the efficiency of impulse transmission and increase the duration that these devices function clinically.
  • the device includes cochlear implants and/or leads that are coated with an anti-scarring agent or a composition that includes an anti-scarring agent.
  • a composition that includes an anti-scarring agent can be infiltrated into the cochlear tissue surrounding the lead.
  • Electrical Stimulation to Promote Bone Growth can be used to stimulate bone growth.
  • the stimulation device may be an electrode and generator having a strain response piezoelectric material which responds to strain by generating a charge to enhance the anchoring of an implanted bone prosthesis to the natural bone. See e.g., U.S. Patent No. 6,143,035. If excessive scar tissue growth or extracellular matrix deposition occurs around the leads, efficacy can be compromised. Electrical bone stimulation devices that release a therapeutic agent able to reduce scarring at the electrode-tissue interface can increase the efficiency of impulse transmission and increase the duration that these devices function clinically.
  • the device includes bone stimulation devices and/or leads that are coated with an anti- scarring agent or a composition that includes an anti-scarring agent.
  • a composition that includes an anti- scarring agent can be infiltrated into the bone tissue surrounding the electrical lead.
  • numerous neurostimulation devices have been described above, all possess similar design features and cause similar unwanted tissue reactions following implantation. It should be obvious to one of skill in the art that commercial neurostimulation devices not specifically sited above as well as next-generation and/or subsequently-developed commercial neurostimulation products are to be anticipated and are suitable for use under the present invention.
  • the neurostimulation device, particularly the lead(s) must be positioned in a very precise manner to ensure that stimulation is delivered to the correct anatomical location in the nervous system.
  • a neurostimulation device can migrate following surgery, or excessive scar (or glial) tissue growth can occur around the implant, which can lead to a reduction in the performance of these devices.
  • Neurostimulator devices that release a therapeutic agent for reducing scarring (or gliosis) at the electrode- tissue interface can be used to increase the efficacy and/or the duration of activity of the implant (particularly for fully-implanted, battery-powered devices).
  • the present invention provides neurostimulator devices that include an anti-scarring (or anti-gliosis) agent or a composition that includes an anti-scarring (or anti-gliosis) agent. Numerous polymeric and non-polymeric delivery systems for use in neurostimulator devices have been described above.
  • compositions can further include one or more fibrosis-inhibiting (or gliosis-inhibiting) agents such that the overgrowth of granulation, fibrous, or gliotic tissue is inhibited or reduced.
  • Methods for incorporating fibrosis-inhibiting (or gliosis-inhibiting) compositions onto or into these neurostimulator devices include: (a) directly affixing to the device, lead and/or the electrode a fibrosis-inhibiting (or gliosis- inhibiting) composition (e.g., by either a spraying process or dipping process as described above, with or without a carrier), (b) directly incorporating into the device, lead and/or the electrode a fibrosis-inhibiting (or gliosis-inhibiting) composition (e.g., by either a spraying process or dipping process as described above, with or without a carrier (c) by coating the device, lead and/or the electrode with a substance such as a hydrogel which may
  • each of these methods illustrates an approach for combining an electrical device with a fibrosis-inhibiting (also referred to herein as an anti- scarring) or gliosis-inhibiting agent according to the present invention.
  • the coating process can be performed in such a manner as to: (a) coat the non-electrode portions of the lead or device; (b) coat the electrode portion of the lead; or (c) coat all or parts of the entire device with the fibrosis-inhibiting (or gliosis-inhibiting) composition.
  • a medical device may be prepared which has a coating, where the coating is, e.g., uniform, non-uniform, continuous, discontinuous, or patterned.
  • a neurostimulation device may include a plurality of reservoirs within its structure, each reservoir configured to house and protect a therapeutic drug. The reservoirs may be formed from divets in the device surface or micropores or channels in the device body.
  • the reservoirs are formed from voids in the structure of the device.
  • the reservoirs may house a single type of drug or more than one type of drug.
  • the drug(s) may be formulated with a carrier (e.g., a polymeric or non-polymeric material) that is loaded into the reservoirs.
  • the filled reservoir can function as a drug delivery depot which can release drug over a period of time dependent on the release kinetics of the drug from the carrier.
  • the reservoir may be loaded with a plurality of layers. Each layer may include a different drug having a particular amount (dose) of drug, and each layer may have a different composition to further tailor the amount of drug that is released from the substrate.
  • the multi-layered carrier may further include a barrier layer that prevents release of the drug(s).
  • the barrier layer can be used, for example, to control the direction that the drug elutes from the void.
  • the coating of the medical device may directly contact the electrical device, or it may indirectly contact the electrical device when there is something, e.g., a polymer layer, that is interposed between the electrical device and the coating that contains the fibrosis-inhibiting agent.
  • the fibrosis-inhibiting (or gliosis-inhibiting) agent can be applied directly or indirectly to the tissue adjacent to the neurostimulator device (preferably near the electrode-tissue interface).
  • the fibrosis-inhibiting (or gliosis inhibiting) agent with or without a polymeric, non- polymeric, or secondary carrier: (a) to the lead and/or electrode surface (e.g., as an injectable, paste, gel or mesh) during the implantation procedure); (b) to the surface of the tissue (e.g., as an injectable, paste, gel, in situ forming gel or mesh) prior to, immediately prior to, or during, implantation of the neurostimulation device, lead and/or electrode; (c) to the surface of the lead and/or electrode and/or the tissue surrounding the implanted lead and/or electrode (e.g., as an injectable, paste, gel, in situ forming gel or mesh) immediately after to the implantation of the neurostimulation device, lead and/or electrode; (d) by topical application of the anti-fibrosis (or gliosis) agent into the anatomical space where the neurostimulation device, lead and/or electrode will be placed (particularly useful
  • Combination therapies i.e., combinations of therapeutic agents and combinations with antithrombotic and/or antiplatelet agents
  • certain polymeric carriers themselves can help prevent the formation of fibrous or gliotic tissue around the neuroimplant. These carriers (to be described shortly) are particularly useful for the practice of this embodiment, either alone, or in combination with a fibrosis (or gliosis) inhibiting composition.
  • the following polymeric carriers can be infiltrated (as described in the previous paragraph) into the vicinity of the electrode-tissue interface and include: (a) sprayable collagen-containing formulations such as COSTASIS and crosslinked derivatized poly( ethylene glycol) -collagen compositions (described, e.g., in U.S.
  • CT3 Patent Nos. 5,874,500 and 5,565,519 and referred to herein as "CT3" (both from Angiotech Pharmaceuticals, Inc., Canada), either alone, or loaded with a fibrosis-inhibiting (or gliosis-inhibiting) agent, applied to the implantation site (or the implant/device surface); (b) sprayable PEG-containing formulations such as COSEAL (Angiotech
  • Neomend, Inc. (Sunnyvale, CA), applied to the implantation site (or the implant/device surface); (j) polysaccharide gels such as the ADCON series of gels (available from Gliatech, Inc., Cleveland, OH) either alone, or loaded with a fibrosis- inhibiting (or gliosis-inhibiting) agent, applied to the implantation site (or the implant/device surface); and/or (k) films, sponges or meshes such as INTERCEED (Gynecare Worldwide, a division of Ethicon, Inc., Somerville, NJ), VICRYL mesh (Ethicon, Inc.), and GELFOAM (Pfizer, Inc., New York, NY) loaded with a fibrosis-inhibiting (or gliosis-inhibiting) agent applied to the implantation site (or the implant/device surface).
  • ADCON series of gels available from Gliatech, Inc., Cleveland, OH
  • a preferred polymeric matrix which can be used to help prevent the formation of fibrous or gliotic tissue around the neuroimplant, either alone or in combination with a fibrosis (or gliosis) inhibiting agent/composition is formed from reactants comprising either one or both of pentaerythritol poly( ethylene glycol)ethertetra-su!fhydryl] (4-armed thiol PEG, which includes structures having a linking group(s) between a sulfhydryl group(s) and the terminus of the polyethylene glycol backbone) and pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG, which again includes structures having a linking group(s) between a NHS group(s) and the terminus of the polyethylene glycol backbone) as reactive reagents.
  • reactants comprising either one or both of pentaerythritol poly( ethylene glycol)ethertetra
  • Another preferred composition comprises either one or both of pentaerythritol poly( ethylene glycoI)ether tetra-amino] (4-armed amino PEG, which includes structures having a linking group(s) between an amino group(s) and the terminus of the polyethylene glycol backbone) and pentaerythritol poly( ethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG, which again includes structures having a linking group(s) between a NHS group(s) and the terminus of the polyethylene glycol backbone) as reactive reagents.
  • Chemical structures for these reactants are shown in, e.g., U.S. Patent 5,874,500.
  • collagen or a collagen derivative is added to the poly( ethylene glycol)-containing reactant(s) to form a preferred crosslinked matrix that can serve as a polymeric carrier for a therapeutic agent or a standalone composition to help prevent the formation of fibrous or gliotic tissue around the neuroimplant.
  • a collagen derivative e.g., methylated collagen
  • any anti-scarring (or anti-gliotic) agent described above may be utilized alone, or in combination, in the practice of this embodiment.
  • the exact dose administered will vary with device size, surface area and design. However, certain principles can be applied in the application of this art.
  • Drug dose can be calculated as a function of dose per unit area (of the portion of the device being coated), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined.
  • the fibrosis-inhibiting (or gliosis-inhibiting) agents used alone or in combination, may be administered under the following dosing guidelines:
  • Drugs are to be used at concentrations that range from a single systemic dose (e.g., the dose used in oral or i.v. administration) to a fraction of a single systemic dose (e.g., 50%, 10%, 5%, or even less than 1 % of the concentration typically used in a single systemic dose application).
  • a single systemic dose e.g., the dose used in oral or i.v. administration
  • a fraction of a single systemic dose e.g. 50%, 10%, 5%, or even less than 1 % of the concentration typically used in a single systemic dose application.
  • the drug is released in effective concentrations for a period ranging from 1 - 90 days.
  • Antimicrotubule agents including taxanes, such as paclitaxel and analogues and derivatives (e.g., docetaxel) thereof, and vinca alkaloids, including vinblastine and vincristine sulfate and analogues and derivatives thereof, should be used under the following parameters: total dose not to exceed 10 mg (range of 0.1 ⁇ g to 10 mg); preferred total dose 1 ⁇ g to 3 mg. Dose per unit area of the device of 0.05 ⁇ g - 10 ⁇ g per mm 2 ; preferred dose/unit area of 0.20 ⁇ g/mm 2 - 5 ⁇ g/mm 2 . Minimum concentration of 10 "9 - 10 "4 M of drug is to be maintained on the device surface.
  • Immunomodulators including sirolimus and everolimus.
  • Sirolimus i.e., rapamycin, RAPAMUNE
  • Total dose not to exceed 10 mg (range of 0.1 ⁇ g to 10 mg); preferred 10 ⁇ g to 1 mg.
  • Minimum concentration of 10 "s - 10 "4 M is to be maintained on the device surface.
  • Everolimus and derivatives and analogues thereof Total dose should not exceed 10 mg (range of 0.1 ⁇ g to 10 mg); preferred 10 ⁇ g to 1 mg.
  • Minimum concentration of 10 "8 - 10 "4 M of everolimus is to be maintained on the device surface.
  • Inosine monophosphate dehydrogenase inhibitors e.g., mycophenolic acid, 1-alpha-25 dihydroxy vitamin D 3
  • analogues and derivatives thereof total dose not to exceed 2000 mg (range of 10.0 ⁇ g to 2000 mg); preferred 10 ⁇ g to 300 mg.
  • the dose per unit area of the device of 1.0 ⁇ g - 1000 ⁇ g per mm 2 ; preferred dose of 2.5 ⁇ g/mm 2 - 500 ⁇ g/mm 2 .
  • Minimum concentration of 10 "8 - 10 "3 M of mycophenolic acid is to be maintained on the device surface.
  • the electrical device may be a cardiac pacemaker device where a pulse generator delivers an electrical impulse to myocardial tissue (often specialized conduction fibres) via an implanted lead in order to regulate cardiac rhythm.
  • electrical leads are composed of a connector assembly, a lead body (i.e., conductor) and an electrode. Electrical leads may be unipolar, in which they are adapted to provide effective therapy with only one electrode. Multi-polar leads are also available, including bipolar, tripolar and quadripolar leads. Electrical leads may also have insulating sheaths which may include polyurethane or silicone-rubber coatings.
  • electrical leads include, without limitation, medical leads, cardiac leads, pacer leads, pacing leads, pacemaker leads, endocardial leads, endocardial pacing leads, cardioversion/defibrillator leads, cardioversion leads, epicardial leads, epicardial defibrillator leads, patch defibrillators, patch leads, electrical patch, transvenous leads, active fixation leads, passive fixation leads and sensing leads
  • CRM devices that utilize electrical leads include: pacemakers, LVAD's, defibrillators, implantable sensors and other electrical cardiac stimulation devices. There are numerous pacemaker devices where the occurrence of a fibrotic reaction will adversely affect the functioning of the device or cause damage to the myocardial tissue.
  • fibrotic encapsulation of the pacemaker lead slows, impairs, or interrupts electrical transmission of the impulse from the device to the myocardium.
  • fibrosis is often found at the electrode-myocardial interfaces in the heart, which may be attributed to electrical injury from focal points on the electrical lead.
  • the fibrotic injury may extend into the tricuspid valve, which may lead to perforation.
  • Fibrosis may lead to thrombosis of the subclavian vein; a condition which may be life-threatening. Electrical leads that release therapeutic agent for reducing scarring at the electrode-tissue interface may help prolong the clinical performance of these devices.
  • fibrosis cause the device to function suboptimally or not at all, it can cause excessive drain on battery life as increased energy is required to overcome the electrical resistance imposed by the intervening scar tissue.
  • fibrotic encapsulation of the sensing components of a rate-responsive pacemaker can impair the ability of the pacemaker to identify and correct rhythm abnormalities leading to inappropriate pacing of the heart or the failure to function correctly when required.
  • Several different electrical pacing devices are used in the treatment of various cardiac rhythm abnormalities including pacemakers, implantable cardioverter defibrillators (ICD), left ventricular assist devices (LVAD), and vagus nerve stimulators (stimulates the fibers of the vagus nerve which in turn innervate the heart).
  • the pulse generating portion of device sends electrical impulses via implanted leads to the muscle (myocardium) or conduction tissue of the heart to affect cardiac rhythm or contraction.
  • Pacing can be directed to one or more chambers of the heart.
  • Cardiac pacemakers may be used to block, mask, or stimulate electrical signals in the heart to treat dysfunctions, including, without limitation, atrial rhythm abnormalities, conduction abnormalities and ventricular rhythm abnormalities.
  • ICDs are used to depolarize the ventricals and re-establish rhythm if a ventricular arrhythmia occurs (such as asystole or ventricular tachycardia) and LVADs are used to assist ventricular contraction in a failing heart.
  • Representative examples of patents which describe pacemakers and pacemaker leads include U.S. Patent Nos. 4,662,382, 4,782,836,
  • cardiac stimulators see e.g., U.S. Patent No. 6,584,351 and 6,115,633
  • pacemakers see e.g., U.S. Patent No. 6,564,099; 6,246,909 and 5,876,423
  • ICDs implantable cardioverter-defibrillators
  • other defibrillator devices see e.g., U.S. Patent No.
  • defibrillator or demand pacer catheters see e.g., U.S. Patent No. 5,476,502
  • Left Ventricular Assist Devices see e.g., U.S. Patent No. 5,503,615.
  • Cardiac rhythm devices, and in particular the lead(s) that deliver the electrical pulsation must be positioned in a very precise manner to ensure that stimulation is delivered to the correct anatomical location in the heart. All, or parts, of a pacing device can migrate following surgery, or excessive scar tissue growth can occur around the lead, which can lead to a reduction in the performance of these devices (as described previously).
  • Cardiac rhythm management devices that release a therapeutic agent for reducing scarring at the electrode-tissue interface can be used to increase the efficacy and/or the duration of activity (particularly for fully-implanted, battery-powered devices) of the implant. Accordingly, the present invention provides cardiac leads that are coated with an anti-scarring agent or a composition that includes an anti- scarring agent.
  • cardiac rhythm management devices and treatments will be described in greater detail including: a) Cardiac Pacemakers Cardiac rhythm abnormalities are extremely common in clinical practice and the incidence increases in frequency with both age and the presence of underlying coronary artery disease or myocardial infarction.
  • a litany of arrythmias exists, but they are generally categorized into conditions where the heart beats too slowly (bradyarrythmias - such heart block, sinus node dysfunction) or too quickly (tachyarrhythmias - such as atrial fibrillation, WPW syndrome, ventricular fibrillation).
  • a pacemaker functions by sending an electrical pulse (a pacing pulse) that travels via an electrical lead to the electrode (at the tip of the lead) which delivers an electrical impulse to the heart that initiates a heartbeat.
  • the leads and electrodes can be located in one chamber (either the right atrium or the right ventricle - called single-chamber pacemakers) or there can be electrodes in both the right atrium and the right ventricle (called dual-chamber pacemakers).
  • Electrical leads may be implanted on the exterior of the heart (e.g., epicardial leads) by a surgical procedure, or they can be connected to the endocardial surface of the heart via a catheter, guidewire or stylet. In some pacemakers, the device assumes the rhythm generating function of the heart and fires at a regular rate.
  • the device merely augments the heart's own pacing function and acts "on demand” to provide pacing assistance as required (called “adaptive- rate” pacemakers); the pacemaker receives feedback on heart rhythm (and hence when to fire) from an electrode sensor located on the lead.
  • Other pacemakers called rate responsive pacemakers, have special sensors that detect changes in body activity (such as movement of the arms and legs, respiratory rate) and adjust pacing up or down accordingly.
  • Numerous pacemakers and pacemaker leads are suitable for use in this invention.
  • the pacing lead may have an increased resistance to fracture by being composed of an elongated coiled conductor mounted within a lumen of a lead body whereby it may be coupled electrically to a stranded conductor.
  • the pacing lead may have a coiled conductor with an insulated sheath, which has a resistance to crush fatigue in the region between the rib and clavicle. See e.g., U.S. Patent No. 5,800,496.
  • the pacing lead may be expandable from a first, shorter configuration to a second, longer configuration by being composed of slideable inner and outer overlapping tubes containing a conductor. See e.g., U.S. Patent No. 5,897,585.
  • the pacing lead may have the means for temporarily making the first portion of the lead body stiffer by using a magnet-rheologic fluid in a cavity that stiffens when exposed to a magnetic field. See e.g., U.S. Patent No. 5,800,497.
  • the pacing lead may be a coil configuration composed of a plurality of wires or wire bundles made from a duplex titanium alloy. See e.g., U.S. Patent No. 5,423,881.
  • the pacing lead may be composed of a wire wound in a coil configuration with the wire composed of stainless steel having a composition of at least 22% nickel and 2% molybdenum. See e.g., U.S. Patent No. 5,433,744.
  • the electrical lead used in the practice of this invention may have an active fixation element for attachment to tissue.
  • the electrical lead may have a rigid fixation helix with microgrooves that are dimensioned to minimize the foreign body response following implantation. See e.g., U.S. Patent No. 6,078,840.
  • the electrical lead may have an electrode/anchoring portion with a dual tapered self-propelling spiral electrode for attachment to vessel wall. See e.g., U.S. Patent No. 5,871 ,531.
  • the electrical lead may have a rigid insulative electrode head carrying a helical electrode. See e.g., U.S. Patent No. 6,038,463.
  • the electrical lead may have an improved anchoring sleeve designed with an introducer sheath to minimize the flow of blood through the sheath during introduction. See e.g., U.S. Patent No. 5,827,296.
  • the electrical lead may be composed of an insulated electrical conductive portion and a lead-in securing section having a longitudinally rigid helical member which may be screwed into tissue. See e.g., U.S. Patent No. 4,000,745.
  • Suitable leads for use in the practice of this invention also include multi-polar leads with multiple electrodes connected to the lead body.
  • the electrical lead may be a multi-electrode lead whereby the lead has two internal conductors and three electrodes with two electrodes coupled by a capacitor integral with the lead. See e.g., U.S. Patent No. 5,824,029.
  • the electrical lead may be a lead body with two straight sections and a bent third section with associated conductors and electrodes whereby the electrodes are bipolar. See e.g., U.S. Patent No. 5,995,876.
  • the electrical lead may be implanted by using a catheter, guidewire or stylet.
  • the electrical lead may be composed of an elongated insulative lead body having a lumen with a conductor mounted within the lead body and a resilient seal having an expandable portion through which a guidewire may pass.
  • pacemakers suitable for the practice of the invention include the KAPPA SR 400 Series single-chamber rate- responsive pacemaker system, the KAPPA DR 400 Series dual-chamber rate- responsive pacemaker system, the KAPPA 900 and 700 Series single-chamber rate-responsive pacemaker system, and the KAPPA 900 and 700 Series dual- chamber rate-responsive pacemaker system by Medtronic, Inc.
  • Medtronic pacemaker systems utilize a variety leads including the CAPSURE Z Novus, CAPSUREFIX Novus, CAPSUREFIX, CAPSURE SP Novus, CAPSURE SP, CAPSURE EPI and the CAPSURE VDD which may be suitable for coating with a fibrosis-inhibiting agent.
  • Pacemaker systems and associated leads that are made by Medtronic are described in, e.g., U.S. Patent Nos. 6,741 ,893; 5,480,441 ; 5,411 ,545; 5,324,310; 5,265,602; 5,265,601 ; 5,241 ,957 and 5,222,506.
  • Medtronic also makes a variety of steroid-eluting leads including those described in, e.g., U.S. Patent Nos. 5,987,746; 6,363,287; 5,800,470; 5,489,294; 5,282,844 and 5,092,332.
  • the INSIGNIA single-chamber and dual- chamber system PULSAR MAX II DR dual-chamber adaptive-rate pacemaker, PULSAR MAX II SR single-chamber adaptive-rate pacemaker, DISCOVERY II DR dual-chamber adaptive-rate pacemaker, DISCOVERY II SR single-chamber adaptive-rate pacemaker, DISCOVERY II DDD dual-chamber pacemaker, and the DISCOVERY II SSI dingle-chamber pacemaker systems made by Guidant Corp. (Indianapolis, IN) are also suitable pacemaker systems for the practice of this invention.
  • the leads from the Guidant pacemaker systems may be suitable for coating with a fibrosis-inhibiting agent. Pacemaker systems and associated leads that are made by Guidant are described in, e.g., U.S.
  • the AFFINITY DR, AFFINITY VDR, AFFINITY SR, AFFINITY DC, ENTITY, IDENTITY, IDENTITY ADX, INTEGRITY, INTEGRITY ⁇ DR, INTEGRITY ADx, MICRONY, REGENCY, TRILOGY, and VERITY ADx pacemaker systems and leads from St. Jude Medical, Inc. (St. Paul, MN) may also be suitable for use with a fibrosis-inhibiting coating to improve electrical transmission and sensing by the pacemaker leads.
  • Pacemaker systems and associated leads that are made by St. Jude Medical are described in, e.g., U.S. Patent Nos. 6,763,266; 6,760,619; 6,535,762; 6,246,909; 6,198,973; 6,183,305; 5,800,468 and 5,716,390.
  • the fibrosis-inhibiting agent may be infiltrated into the region around the electrode-cardiac muscle interface under the present invention. It should be obvious to one of skill in the art that commercial pacemakers not specifically sited as well as next-generation and/or subsequently developed commercial pacemaker products are to be anticipated and are suitable for use under the present invention.
  • the leads must be accurately positioned adjacent to the targeted cardiac muscle tissue. If excessive scar tissue growth or extracellular matrix deposition occurs around the leads, efficacy can be compromised.
  • Pacemaker leads that release a therapeutic agent able to reduce scarring at the electrode-tissue and/or sensor- tissue interface can increase the efficiency of impulse transmission and rhythm sensing, thereby increasing efficacy and battery longevity.
  • the device includes pacemaker leads that are coated with an anti-scarring agent or a composition that includes an anti-scarring agent.
  • a composition that includes an anti-scarring agent can be infiltrated into the myocardial tissue surrounding the lead.
  • ICD Implantable Cardioverter Defibrillator
  • ICD Implantable cardioverter defibrillator
  • An ICD consists of a mini-computer powered by a battery which is connected to a capacitor to helps the ICD charge and store enough energy to deliver therapy when needed.
  • the ICD uses sensors to monitor the activity of the heart and the computer analysizes the data to determine when and if an arrhythmia is present.
  • An ICD lead which is inserted via a vein (called “transvenous” leads; in some systems the lead is implanted surgically - called an epicardial lead - and sewn onto the surface of the heart), connects into the pacing/computer unit.
  • the lead which is usually placed in the right ventricle, consists of an insulated wire and an electrode tip that contains a sensing component (to detect cardiac rhythm) and a shocking coil.
  • a single-chamber ICD has one lead placed in the ventricle which defibrillates and paces the ventricle, while a dual-chamber ICD defibrillates the ventricle and paces the atrium and the ventricle.
  • an additional lead is required and is placed under the skin next to the rib cage or on the surface of the heart.
  • a second coil is placed in the atrium to treat atrial tachycardia, atrial fibrillation and other arrhythmias. If a tachyarrhythmia is detected, a pulse is generated and propagated via the lead to the shocking coil which delivers a charge sufficient to depolarize the muscle and cardiovert or defibrillate the heart.
  • the defibrillator lead may be a linear assembly of sensors and coils formed into a loop which includes a conductor system for coupling the loop system to a pulse generator. See e.g., U.S. Patent No. 5,897,586.
  • the defibrillator lead may have an elongated lead body with an elongated electrode extending from the lead body, such that insulative tubular sheaths are slideably mounted around the electrode.
  • the defibrillator lead may be a temporary lead with a mounting pad and a temporarily attached conductor with an insulative sleeve whereby a plurality of wire electrodes are mounted. See e.g., U.S. Patent No. 5,849,033.
  • Other defibrillator leads are described in, e.g., U.S. Patent No. 6,052,625.
  • the electrical lead may be adapted to be used for pacing, defibrillating or both applications.
  • the electrical lead may be an electrically insulated, elongated, lead body sheath enclosing a plurality of lead conductors that are separated from contacting one another. See e.g., U.S. Patent No. 6,434,430.
  • the electrical lead may be composed of an inner lumen adapted to receive a stiffening member (e.g., guide wire) that delivers fluoro- visible media. See e.g., U.S. Patent No. 6,567,704.
  • the electrical lead may be a catheter composed of an elongated, flexible, electrically nonconductive probe contained within an electrically conductive pathway that transmits electrical signals, including a defibrillation pulse and a pacer pulse, depending on the need that is sensed by a governing element. See e.g., U.S. Patent No. 5,476,502.
  • the electrical lead may have a low electrical resistance and good mechanical resistance to cyclical stresses by being composed of a conductive wire core formed into a helical coil covered by a layer of electrically conductive material and an electrically insulating sheath covering. See e.g., U.S. Patent No. 5,330,521.
  • ICDs suitable for the practice of the invention include the GEM III DR dual-chamber ICD, GEM III VR ICD, GEM II ICD, GEM ICD, GEM III AT atrial and ventricular arrhythmia ICD, JEWEL AF dual-chamber ICD, MICRO JEWEL ICD, MICRO JEWEL II ICD, JEWEL Plus ICD, JEWEL ICD, JEWEL ACTIVE CAN ICD, JEWEL PLUS ACTIVE CAN ICD, MAXIMO DR ICD, MAXIMO VR ICD, MARQUIS DR ICD, MARQUIS VR system, and the INTRINSIC dual-chamber ICD by Medtronic, Inc.
  • Medtronic ICD systems utilize a variety leads including the SPRINT FIDELIS, SPRINT QUATRO SECURE steroid-eluting bipolar lead, Subcutaneous Lead System Model 6996SQ subcutaneous lead, TRANSVENE 6937A transvenous lead, and the 6492 Unipolar Atrial Pacing Lead which may be suitable for coating with a fibrosis-inhibiting agent.
  • ICD systems and associated leads that are made by Medtronic are described in, e.g., U.S. Patent Nos. 6,038,472; 5,849,031 ; 5,439,484; 5,314,430; 5,165,403; 5,099,838 and 4,708,145.
  • Guidant sells the FLEXTEND Bipolar Leads, EASYTRAK Lead System, FINELINE Leads, and ENDOTAK RELIANCE ICD Leads.
  • ICD systems and associated leads that are made by Guidant are described in, e.g., U.S. Patent Nos. 6,574,505; 6,018,681 ; 5,697,954; 5,620,451 ; 5,433,729; 5,350,404; 5,342,407; 5,304,139 and 5,282,837. Biotronik, Inc.
  • Jude Medical may also be suitable for use with a fibrosis-inhibiting coating to improve electrical transmission and sensing by the ICD leads (see e.g., U.S. Patent Nos. 5,944,746; 5,722,994; 5,662,697; 5,542,173; 5,456,706 and 5,330,523).
  • the fibrosis-inhibiting agent may be infiltrated into the region around the electrode-cardiac muscle interface under the present invention. It should be obvious to one of skill in the art that commercial ICDs not specifically sited as well as next-generation and/or subsequently developed commercial ICD products are to be anticipated and are suitable for use under the present invention.
  • the leads must be accurately positioned adjacent to the targeted cardiac muscle tissue. If excessive scar tissue growth or extracellular matrix deposition occurs around the leads, efficacy can be compromised. ICD leads that release a therapeutic agent able to reduce scarring at the electrode-tissue and/or sensor-tissue interface, can increase the efficiency of impulse transmission and rhythm sensing, thereby increasing efficacy, preventing inappropriate cardioversion, and improving battery longevity.
  • the device includes ICD leads that are coated with an anti-scarring agent or a composition that includes an anti-scarring agent.
  • a composition that includes an anti-scarring agent can be infiltrated into the myocardial tissue surrounding the lead.
  • a neurostimulation device may be used to stimulate the vagus nerve and affect the rhythm of the heart. Since the vagus nerve provides innervation to the heart, including the conduction system (including the SA node), stimulation of the vagus nerve may be used to treat conditions such as supraventricular arrhythmias, angina pectoris, atrial tachycardia, atrial flutter, atrial fibrillation and other arrhythmias that result in low cardiac output.
  • a bipolar electrical lead is surgically implanted such that it transmits electrical stimulation from the pulse generator to the left vagus nerve in the neck.
  • the pulse generator is an implanted, lithium carbon monofluoride battery-powered device that delivers a precise pattern of stimulation to the vagus nerve.
  • the pulse generator can be programmed (using a programming wand) by the cardiologist to treat a specific arrhythmia. Products such as these have been described, for example, in U.S.
  • the neurostimulator may be a vagal-stimulation apparatus which generates pulses at a frequency that varies automatically based on the excitation rates of the vagus nerve. See e.g., U.S. Patent Nos. 5,916,239 and 5,690,681.
  • the neurostimulator may be an apparatus that detects characteristics of tachycardia based on an electrogram and delivers a preset electrical stimulation to the nervous system to depress the heart rate. See e.g., U.S. Patent No. 5,330,507.
  • the neurostimulator may be an implantable heart stimulation system composed of two sensors, one for atrial signals and one for ventricular signals, and a pulse generator and control unit, to ensure sympatho-vagal stimulation balance. See e.g., U.S. Patent No.
  • the neurostimulator may be a device that applies electrical pulses to the vagus nerve at a programmable frequency that is adjusted to maintain a lower heart rate. See e.g., U.S. Patent No. 6,473,644.
  • the neurostimulator may provide electrical stimulation to the vagus nerve to induce changes to electroencephalogram readings as a treatment for epilepsy, while controlling the operation of the heart within normal parameters. See e.g., U.S. Patent 6,587,727.
  • a commercial example of a VNS system is the product produced by Cyberonics Inc.
  • VNS devices that release a therapeutic agent able to reducing scarring at the electrode-tissue interface can increase the efficiency of impulse transmission and increase the duration that these devices function clinically.
  • the device includes VNS devices and/or leads that are coated with an anti-scarring agent or a composition that includes an anti- scarring agent.
  • a composition that includes an anti-scarring agent can be infiltrated into the tissue surrounding the vagus nerve where the lead will be implanted.
  • cardiac rhythm management (CRM) devices have been described above, all possess similar design features and cause similar unwanted fibrous tissue reactions following implantation.
  • the CRM device particularly the lead(s), must be positioned in a very precise manner to ensure that stimulation is delivered to the correct anatomical location within the atrium and/or ventricle. All, or parts, of a CRM device can migrate following surgery, or excessive scar tissue growth can occur around the implant, which can lead to a reduction in the performance of these devices.
  • CRM devices that release a therapeutic agent for reducing scarring at the electrode-tissue interface can be used to increase the efficacy and/or the duration of activity of the implant (particularly for fully-implanted, battery-powered devices).
  • the present invention provides CRM devices that include a fibrosis- inhibiting agent or a composition that includes a fibrosis-inhibiting agent.
  • compositions can further include one or more fibrosis-inhibiting agents such that the overgrowth of granulation or fibrous tissue is inhibited or reduced.
  • Methods for incorporating fibrosis-inhibiting compositions onto or into CRM devices include: (a) directly affixing to the CRM device, lead and/or electrode a fibrosis-inhibiting composition (e.g., by either a spraying process or dipping process as described above, with or without a carrier), (b) directly incorporating into the CRM device, lead and/or electrode a fibrosis-inhibiting composition (e.g., by either a spraying process or dipping process as described above, with or without a carrier (c) by coating the CRM device, lead and/or electrode with a substance such as a hydrogel which will in turn absorb the fibrosis-inhibiting composition, (d) by interweaving fibrosis-inhibiting composition coated thread (or the
  • each of these methods illustrates an approach for combining an electrical device with a fibrosis-inhibiting (also referred to herein as an anti-scarring) or gliosis-inhibiting agent according to the present invention.
  • the coating process can be performed in such a manner as to: (a) coat the non-electrode portions of the lead; (b) coat the electrode portion of the lead; or (c) coat all or parts of the entire device with the fibrosis-inhibiting composition.
  • the fibrosis-inhibiting agent can be mixed with the materials that are used to make the CRM device, lead and/or electrode such that the fibrosis- inhibiting agent is incorporated into the final product.
  • a medical device may be prepared which has a coating, where the coating is, e.g., uniform, non-uniform, continuous, discontinuous, or patterned.
  • a CRM device may include a plurality of reservoirs within its structure, each reservoir configured to house and protect a therapeutic drug.
  • the reservoirs may be formed from divets in the device surface or micropores or channels in the device body.
  • the reservoirs are formed from voids in the structure of the device.
  • the reservoirs may house a single type of drug or more than one type of drug.
  • the drug(s) may be formulated with a carrier (e.g., a polymeric or non-polymeric material) that is loaded into the reservoirs.
  • the filled reservoir can function as a drug delivery depot which can release drug over a period of time dependent on the release kinetics of the drug from the carrier.
  • the reservoir may be loaded with a plurality of layers. Each layer may include a different drug having a particular amount (dose) of drug, and each layer may have a different composition to further tailor the amount of drug that is released from the substrate.
  • the multi-layered carrier may further include a barrier layer that prevents release of the drug(s). The barrier layer can be used, for example, to control the direction that the drug elutes from the void.
  • the coating of the medical device may directly contact the electrical device, or it may indirectly contact the electrical device when there is something, e.g., a polymer layer, that is interposed between the electrical device and the coating that contains the fibrosis-inhibiting agent.
  • the fibrosis-inhibiting agent can be applied directly or indirectly to the tissue adjacent to the CRM device (preferably near the electrode-tissue interface).
  • the fibrosis-inhibiting agent with or without a polymeric, non- polymeric, or secondary carrier: (a) to the lead and/or electrode surface (e.g., as an injectable, paste, gel, or mesh) during the implantation procedure; (b) to the surface of the tissue (e.g., as an injectable, paste, gel, in situ forming gel, or mesh) prior to, immediately prior to, or during, implantation of the CRM device and/or the lead; (c) to the surface of the CRM lead and/or electrode and/or to the tissue surrounding the implanted lead or electrode (e.g., as an injectable, paste, gel, in situ forming gel, or mesh) immediately after the implantation of the CRM device, lead and/or electrode; (d) by topical application of the anti-fibrosis agent into the anatomical space where the CRM device, lead and/or electrode will be placed (particularly useful for this embodiment is the use of polymeric carriers which release the fibrosis-inhibiting agent over a period
  • Combination therapies i.e., combinations of therapeutic agents and combinations with antithrombotic and/or antiplatelet agents
  • certain polymeric carriers themselves can help prevent the formation of fibrous tissue around the CRM lead and electrode. These carriers (to be described shortly) are particularly useful for the practice of this embodiment, either alone, or in combination with a fibrosis-inhibiting composition.
  • the following polymeric carriers can be infiltrated (as described in the previous paragraph) into the vicinity of the CRM device, lead and/or electrode-tissue interface and include: (a) sprayable collagen-containing formulations such as COSTASIS and CT3, either alone, or loaded with a fibrosis-inhibiting agent, applied to the implantation site (or the implant/device surface); (b) sprayable PEG-containing formulations such as COSEAL, FOCALSEAL, SPRAYGEL or DURASEAL, either alone, or loaded with a fibrosis-inhibiting agent, applied to the implantation site (or the implant/device surface); (c) fibrinogen-containing formulations such as FLOSEAL or TISSEAL, either alone, or loaded with a fibrosis-inhibiting agent, applied to the implantation site (or the implant/device surface); (d) hyaluronic acid-containing formulations such as RESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFIL
  • a preferred polymeric matrix which can be used to help prevent the formation of fibrous or gliotic tissue around the CRM lead and electrode, either alone or in combination with a fibrosis (or gliosis) inhibiting agent/composition is formed from reactants comprising either one or both of pentaerythritol poly( ethylene glycol)ethertetra-sulfhydryl] (4-armed thiol PEG, which includes structures having a linking group(s) between a sulfhydryl group(s) and the terminus of the polyethylene glycol backbone) and pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG, which again includes structures having a linking group(s) between a NHS group(s) and the terminus of the polyethylene glycol backbone) as reactive reagents.
  • reactants comprising either one or both of pentaerythritol poly( ethylene glycol)ethertetra
  • Another preferred composition comprises either one or both of pentaerythritol poly( ethylene glycol)ether tetra-amino] (4-armed amino PEG, which includes structures having a linking group(s) between an amino group(s) and the terminus of the polyethylene glycol backbone) and pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG, which again includes structures having a linking group(s) between a NHS group(s) and the terminus of the polyethylene glycol backbone) as reactive reagents.
  • Chemical structures for these reactants are shown in, e.g., U.S. Patent 5,874,500.
  • collagen or a collagen derivative is added to the poly( ethylene glycol)-containing reactant(s) to form a preferred crosslinked matrix that can serve as a polymeric carrier for a therapeutic agent or a stand-alone composition to help prevent the formation of fibrous or gliotic tissue around the CRM lead and electrode.
  • a collagen derivative e.g., methylated collagen
  • any anti-scarring agent described herein may be utilized alone, or in combination, in the practice of this embodiment.
  • leads and electrodes are made in a variety of configurations and sizes, the exact dose administered may vary with device size, surface area and design. However, certain principles can be applied in the application of this art.
  • Drug dose can be calculated as a function of dose per unit area (of the portion of the device being coated), total drug dose administered can be measured, and appropriate surface concentrations of active drug can be determined.
  • the fibrosis-inhibiting agents used alone or in combination, may be administered under the following dosing guidelines:
  • Drugs are to be used at concentrations that range from several times more than a single systemic dose (e.g., the dose used in oral or i.v. administration) to a fraction of a single systemic dose (e.g., 10%, 5%, or even less than 1 % of the concentration typically used in a single systemic dose application).
  • a single systemic dose e.g., the dose used in oral or i.v. administration
  • a fraction of a single systemic dose e.g., 10%, 5%, or even less than 1 % of the concentration typically used in a single systemic dose application.
  • the drug is released in effective concentrations for a period ranging from 1 - 90 days.
  • Antimicrotubule agents including taxanes, such as paclitaxel and analogues and derivatives (e.g., docetaxel) thereof, and vinca alkaloids, including vinblastine and vincristine sulfate and analogues and derivatives thereof, should be used under the following parameters: total dose not to exceed 10 mg (range of 0.1 ⁇ g to 10 mg); preferred total dose 1 ⁇ g to 3 mg. Dose per unit area of the device of 0.1 ⁇ g - 10 ⁇ g per mm 2 ; preferred dose/unit area of 0.25 ⁇ g/mm 2 - 5 ⁇ g/mm 2 . Minimum concentration of 10 "8 - 10 " 4 M of drug is to be maintained on the device surface.
  • Immunomodulators including sirolimus and everolimus.
  • Sirolimus i.e., rapamycin, RAPAMUNE
  • Total dose not to exceed 10 mg (range of 0.1 ⁇ g to 10 mg); preferred 10 ⁇ g to 1 mg.
  • Minimum concentration of 10 "8 - 10 "4 M is to be maintained on the device surface.
  • Everolimus and derivatives and analogues thereof Total dose should not exceed 10 mg (range of 0.1 ⁇ g to 10 mg); preferred 10 ⁇ g to 1 mg.
  • Minimum concentration of 10 "8 - 10 "4 M of everolimus is to be maintained on the device surface.
  • Inosine monophosphate dehydrogenase inhibitors e.g., mycophenolic acid, 1-alpha-25 dihydroxy vitamin D 3
  • analogues and derivatives thereof total dose not to exceed 2000 mg (range of 10.0 ⁇ g to 2000 mg); preferred 10 ⁇ g to 300 mg.
  • the dose per unit area of the device of 1.0 ⁇ g - 1000 ⁇ g per mm 2 ; preferred dose of 2.5 ⁇ g/mm 2 - 500 ⁇ g/mm 2 .
  • Minimum concentration of 10 "8 - 10 "3 M of mycophenolic acid is to be maintained on the device surface.
  • therapeutic agents for Use with Electrical Medical Devices and Implants
  • numerous therapeutic agents are - potentially suitable to inhibit fibrous (or glial) tissue accumulation around the device bodies, leads and electrodes of implantable electrical devices, e.g., neurostimulation and cardiac rhythm management devices.
  • the invention provides for devices that include an agent that inhibits this tissue accumulation in the vicinity of the device, i.e., between the medical device and the host into which the medical device is implanted.
  • the agent is therefore effective for this goal, is present in an amount that is effective to achieve this goal, and is present at one or more locations that allow for this goal to be achieved, and the device is designed to allow the beneficial effects of the agent to occur.
  • these therapeutic agents can be used alone, or in combination, to prevent scar (or glial) tissue build-up in the vicinity of the electrode-tissue interface in order to improve the clinical performance and longevity of these implants.
  • Suitable fibrosis or gliosis-inhibiting agents may be readily identified based upon in vitro and in vivo (animal) models, such as those provided in Examples 38-51.
  • Agents which inhibit fibrosis can also be identified through in vivo models including inhibition of intimal hyperplasia development in the rat balloon carotid artery model (Examples 43 and 51).
  • the assays set forth in Examples 42 and 50 may be used to determine whether an agent is able to inhibit cell proliferation in fibroblasts and/or smooth muscle cells.
  • the agent has an IC 50 for inhibition of cell proliferation within a range of about 10 ⁇ 6 to about 10 "10 M.
  • the assay set forth in Example 46 may be used to determine whether an agent may inhibit migration of fibroblasts and/or smooth muscle cells.
  • the agent has an IC- 50 for inhibition of cell migration within a range of about 10 "6 to about 10 "9 M.
  • Assays set forth herein may be used to determine whether an agent is able to inhibit inflammatory processes, including nitric oxide production in macrophages (Example 38), and/or TNF-alpha production by macrophages (Example 39), and/or IL-1 beta production by macrophages (Example 47), and/or IL-8 production by macrophages (Example 48), and/or inhibition of MCP- 1 by macrophages (Example 49).
  • the agent has an IC 0 for inhibition of any one of these inflammatory processes within a range of about 10 "6 to about 10 "10 M.
  • the assay set forth in Example 44 may be used to determine whether an agent is able to inhibit MMP production.
  • the agent has an IC 50 for inhibition of MMP production within a range of about 10 "4 to about 10 "8 M.
  • the assay set forth in Example 45 (also known as the CAM assay) may be used to determine whether an agent is able to inhibit angiogenesis.
  • the agent has an IC 50 for inhibition of angiogenesis within a range of about 10 "6 to about 10 "10 M.
  • Agents which reduce the formation of surgical adhesions may be identified through in vivo models including the rabbit surgical adhesions model (Example 41) and the rat caecal sidewall model (Example 40).
  • the pharmacologically active compound is an angiogenesis inhibitor (e.g., 2-ME (NSC-659853), PI-88 (D-mannose, 0-6-0- phosphono-alpha-D-mannopyranosyl-(1-3)-0-alpha-D-mannopyranosyl-(1-3)- 0-alpha-D-mannopyranosyl-(1-3)-0-alpha-D-mannopyranosyl-(1-2)- hydrogen sulphate), thalidomide (1 H-isoindole-1 ,3(2H)-dione, 2-(2,6-dioxo-3-piperidinyl
  • the pharmacologically active compound is a 5-lipoxygenase inhibitor or antagonist (e.g., Wy-50295 (2- naphthaleneacetic acid, alpha-methyl-6-(2-quinolinylmethoxy)-, (S)-), ONO-LP- 269 (2,11 ,14-eicosatrienamide, N-(4-hydroxy-2-(1 H-tetrazol-5-yl)-8-quinolinyl)-, (E,Z,Z)-), licofelone (1 H-pyrrolizine-5-acetic acid, 6-(4-chlorophenyl)-2,3- dihydro-2,2-dimethyl-7-phenyl-), CMI-568 (urea, N-butyl-N-hydroxy-N'-(4-(3- (methylsulfonyl)-2-propoxy-5-(tetrahydro-5-(3,4,5-trime
  • a 5-lipoxygenase inhibitor or antagonist e.g.,
  • the pharmacologically active compound is a chemokine receptor antagonist which inhibits one or more subtypes of CCR (1 , 3, and 5) (e.g., ONO-4128 (1,4,9-triazaspiro(5.5)undecane-2,5-dione, 1- butyl-3-(cyclohexylmethyl)-9-((2,3-dihydro-1 ,4-benzodioxin-6-yl)methyl-), L-381 , CT-112 (L-arginine, L-threonyl-L-threonyl-L-seryl-L-glutaminyl-L-valyl-L-arginyl- L-prolyl-), AS-900004, SCH-C, ZK-811752, PD-172084, UK-427857, SB- 380732, vMIP II, SB-265610, DPC-168,
  • chemokine receptor antagonist which inhibits one or more subtypes of CCR (1 , 3,
  • chemokine receptor antagonists include a-lmmunokine-NNS03, BX-471 , CCX-282, Sch-350634; Sch-351125; Sch-417690; SCH-C, and analogues and derivatives thereof.
  • the pharmacologically active compound is a cell cycle inhibitor.
  • Representative examples of such agents include taxanes (e.g., paclitaxel (discussed in more detail below) and docetaxel) (Schiff et al., Nature 277:665-667, 1979; Long and Fairchild, Cancer Research 54:4355-4361 , 1994; Ringel and Horwitz, J. Nat'l Cancer Inst. 83(4):288-291 , 1991 ; Pazdur et al., Cancer Treat. Rev. 79(40):351-386, 1993), etanidazole, nimorazole (B.A. Chabner and D.L. Longo.
  • Nitroimidazole derivative, production thereof, and radiosensitizer containing the same as active ingredient U.S. Patent No. 5,270,330, Dec 14, 1993; T. Suzuki. 2-Nitroimidazole derivative, production thereof and radiosensitizer containing the same as active ingredient; Patent EP 0 513 351 B1 , Jan. 24, 1991), fluorine-containing nitroazole derivatives (T. Kagiya. Fluorine-containing nitroazole derivatives and radiosensitizer comprising the same.
  • copper M.J. Abrams. Copper Radiosensitizers.
  • Heterocyclic compound derivative, its production and radiosensitizer containing said derivative as active ingredient Publication Number 63170375 A (Japan), Jan. 7, 1987), fluorine containing 3-nitro-1 ,2,4- triazole (T. Kagitani et al. Novel fluorine-containing 3-nitro-1 ,2,4-triazole and radiosensitizer containing same compound.
  • Radiosensitizer for Hypoxic cell Publication Number 61010511 A (Japan), Jun. 26, 1984), Nitrothiazole (T. Kagitani et al. Radiation-sensitizing agent. Publication Number 61167616 A (Japan) Jan. 22, 1985), imidazole derivatives (S. Inayma et al. Imidazole derivative. Publication Number 6203767 A (Japan) Aug. 1 ,1985; Publication Number 62030768 A (Japan) Aug. 1 , 1985;
  • camptothecin Ewend M.G. et al. Local delivery of chemotherapy and concurrent external beam radiotherapy prolongs survival in metastatic brain tumor models. Cancer Research 56(22):5217-5223, 1996) and paclitaxel (Tishler R.B. et al. Taxol: a novel radiation sensitizer. International Journal of Radiation Oncology and Biological Physics 22(3):613- 617, 1992).
  • a number of the above-mentioned cell cycle inhibitors also have a wide variety of analogues and derivatives, including, but not limited to, cisplatin, cyclophosphamide, misonidazole, tiripazamine, nitrosourea, mercaptopurine, methotrexate, fluorouracil, epirubicin, doxorubicin, vindesine and etoposide.
  • Analogues and derivatives include (CPA) 2 Pt(DOLYM) and (DACH)Pt(DOLYM) cisplatin (Choi et al., Arch. Pharmacal Res. 22(2): 151-156, 1999), Cis-
  • gem-diphosphonate cisplatin analogues (FR 2683529), (meso-1 ,2-bis(2,6-dichloro-4-hydroxyplenyl)ethylenediamine) dichloroplatinum(ll) (Bednarski et al., J. Med. Chem. 35(23):4479-85, 1992), cisplatin analogues containing a tethered dansyl group (Hartwig et al., J. Am. Chem. Soc. 774(21):8292-3, 1992), platinum(ll) polyamines (Siegmann et al., Inorg. Mel-Containing Polym.
  • methotrexate tetrahydroquinazoline analogue (Gangjee, et al., J. Heterocycl. Chem. 32(1 ):243-8, 1995), N-( ⁇ -aminoacyl) methotrexate derivatives (Cheung et al., Pteridines 3(1-2):101-2, 1992), biotin methotrexate derivatives (Fan et al., Pteridines 3(1-2):131-2, 1992), D-glutamic acid or D-erythrou, threo-4- fluoroglutamic acid methotrexate analogues (McGuire et al., Biochem. Pharmacol.
  • Pteridines FolicAcid Deriv. > 1154-7, 1989
  • N-(L- ⁇ -aminoacyl) methotrexate derivatives Cheung et al., Heterocycles 28(2):751-8, 1989
  • meta and ortho isomers of aminopterin Rosowsky et al., J. Med. Chem. 32(12):2582, 1989
  • hydroxymethyl methotrexate DE 267495
  • ⁇ -fluoromethotrexate McGuire et al., Cancer Res. 49(16):4517-25, 1989
  • polyglutamyl methotrexate derivatives Kumar et al., Cancer Res.
  • the cell cycle inhibitor is paclitaxel, a compound which disrupts mitosis (M-phase) by binding to tubulin to form abnormal mitotic spindles or an analogue or derivative thereof.
  • paclitaxel is a highly derivatized diterpenoid (Wani et al., J. Am. Chem. Soc.
  • Taxus brevifolia Pacific Yew
  • Taxomyces Andreanae and Endophytic Fungus of the Pacific Yew Stierle et. al., Science 60:214-216, 1993.
  • “Paclitaxel” (which should be understood herein to include formulations, prodrugs, analogues and derivatives such as, for example, TAXOL (Bristol Myers Squibb, New York, NY, TAXOTERE (Aventis Pharmaceuticals, France), docetaxel, 10-desacetyl analogues of paclitaxel and 3'N-desbenzoyl-3'N-t- butoxy carbonyl analogues of paclitaxel) may be readily prepared utilizing techniques known to those skilled in the art (see, e.g., Schiff et.
  • paclitaxel derivatives or analogues include 7-deoxy-docetaxol, 7,8-cyclopropataxanes, N-substituted 2-azetidones, 6,7-epoxy paclitaxels, 6,7-modified paclitaxels, 10-desacetoxytaxol, 10- deacetyltaxol (from 10-deacetylbaccatin III), phosphonooxy and carbonate derivatives of taxol, taxol 2',7-di(sodium 1 ,2-benzenedicarboxyIate, 10- desacetoxy-11 ,12-dihydrotaxol-10,12(18)-diene derivatives, 10- desacetoxytaxol, Protaxol (2'-and/or 7-O-ester derivatives), (2'-and/or 7-0- carbonate derivatives), asymmetric synthesis of taxol side chain, fluoro taxols, 9-deoxotaxane, (13-acety
  • a side-chain (labeled "A" in the diagram) is desirably present in order for the compound to have good activity as a cell cycle inhibitor.
  • compounds having this structure include paclitaxel (Merck Index entry 7117), docetaxol (TAXOTERE, Merck Index entry 3458), and 3'- desphenyl-3'-(4-ntirophenyl)-N-debenzoyl-N-(t-butoxycarbonyl)-10- deacetyltaxol.
  • suitable taxanes such as paclitaxel and its analogues and derivatives are disclosed in U.S. Patent No. 5,440,056 as having the structure (C2):
  • X may be oxygen (paclitaxel), hydrogen (9-deoxy derivatives), thioacyl, or dihydroxyl precursors;
  • Ri is selected from paclitaxel or TAXOTERE side chains or alkanoyl of the formula (C3)
  • R 7 is selected from hydrogen, alkyl, phenyl, alkoxy, amino, phenoxy (substituted or unsubstituted);
  • Rs is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, phenyl (substituted or unsubstituted), alpha or beta- naphthyl;
  • Rg is selected from hydrogen, alkanoyl, substituted alkanoyl, and aminoalkanoyl; where substitutions refer to hydroxyl, sulfhydryl, allalkoxyl, carboxyl, halogen, thioalkoxyl, N,N-dimethylamino, alkylamino, dialkylamino, nitro, and -OS0 3 H, and/or may refer to groups containing such substitutions;
  • R 2 is selected from hydrogen or oxygen-containing groups, such as hydrogen, hydroxyl, alkoyl, alkanoyloxy, aminoalkano
  • the paclitaxel analogues and derivatives useful as cell cycle inhibitors are disclosed in PCT International Patent Application No. WO 93/10076.
  • the analogue or derivative should have a side chain attached to the taxane nucleus at C- ⁇ 3 , as shown in the structure below (formula C4), in order to confer antitumor activity to the taxane.
  • WO 93/10076 discloses that the taxane nucleus may be substituted at any position with the exception of the existing methyl groups.
  • the substitutions may include, for example, hydrogen, alkanoyloxy, alkenoyloxy, aryloyloxy.
  • oxo groups may be attached to carbons labeled 2, 4, 9, and/or 10.
  • an oxetane ring may be attached at carbons 4 and 5.
  • an oxirane ring may be attached to the carbon labeled 4.
  • the taxane-based cell cycle inhibitor useful in the present invention is disclosed in U.S. Patent 5,440,056, which discloses 9- deoxo taxanes.
  • the taxane ring may be substituted at the carbons labeled 1 , 7 and 10 (independently) with H, OH, O-R, or O-CO-R where R is an alkyl or an aminoalkyl. As well, it may be substituted at carbons labeled 2 and 4 (independently) with aryol, alkanoyl, aminoalkanoyl or alkyl groups.
  • the side chain of formula (C3) may be substituted at R 7 and Rs (independently) with phenyl rings, substituted phenyl rings, linear alkanes/alkenes, and groups containing H, O or N.
  • R g may be substituted with H, or a substituted or unsubstituted alkanoyl group.
  • Taxanes in general, and paclitaxel is particular is considered to function as a cell cycle inhibitor by acting as an anti-microtubule agent, and more specifically as a stabilizer. These compounds have been shown useful in the treatment of proliferative disorders, including: non-small cell (NSC) lung; small cell lung; breast; prostate; cervical; endometrial; head and neck cancers.
  • NSC non-small cell
  • the anti-microtuble agent is albendazole (carbamic acid, [5-(propylthio)-1 H-benzimidazol-2-yl]-, methyl ester), LY-355703 (1 ,4-dioxa-8, 11 -diazacyclohexadec-13-ene-2, 5,9,12-tetrone, 10-[(3-chloro-4-methoxyphenyl)methyl]-6,6-dimethyl-3-(2-methylpropyl)-16- [(1S)-1-[(2S,3R)-3-phenyloxiranyl]ethyl]-, (3S,10R,13E,16S)-), vindesine (vincaleukoblastine, 3-(aminocarbonyl)-04-deacetyl-3-de(methoxycarbonyl)-), or WA.Y-174286
  • the cell cycle inhibitor is a vinca alkaloid. Vin
  • RT can be a formyl or methyl group or alternately H.
  • Ri can also be an alkyl group or an aldehyde-substituted alkyl (e.g., CH 2 CHO).
  • R 2 is typically a CH 3 or NH 2 group. However it can be alternately substituted with a lower alkyl ester or the ester linking to the dihydroindole core may be substituted with C(0)-R where R is NH 2 , an amino acid ester or a peptide ester.
  • R 3 is typically C(0)CH 3 , CH 3 or H.
  • a protein fragment may be linked by a bifunctional group, such as maleoyl amino acid.
  • R 3 can also be substituted to form an alkyl ester which may be further substituted.
  • R 4 may be -CH 2 - or a single bond.
  • R 5 and Re may be H, OH or a lower alkyl, typically -CH 2 CH 3 .
  • R 6 and R 7 may together form an oxetane ring.
  • R 7 may alternately be H.
  • Further substitutions include molecules wherein methyl groups are substituted with other alkyl groups, and whereby unsaturated rings may be derivatized by the addition of a side group such as an alkane, alkene, alkyne, halogen, ester, amide or amino group.
  • Exemplary vinca alkaloids are vinblastine, vincristine, vincristine sulfate, vindesine, and vinorelbine, having the structures:
  • Analogues typically require the side group (shaded area) in order to have activity.
  • These compounds are thought to act as cell cycle inhibitors by functioning as anti-microtubule agents, and more specifically to inhibit polymerization. These compounds have been shown useful in treating proliferative disorders, including NSC lung; small cell lung; breast; prostate; brain; head and neck; retinoblastoma; bladder; and penile cancers; and soft tissue sarcoma.
  • the cell cycle inhibitor is a camptothecin, or an anolog or derivative thereof. Camptothecins have the following general structure.
  • X is typically O, but can be other groups, e.g., NH in the case of 21-lactam derivatives.
  • Ri is typically H or OH, but may be other groups, e.g., a terminally hydroxylated C ⁇ -3 alkane.
  • R 2 is typically H or an amino containing group such as (CH 3 ) NHCH 2 , but may be other groups e.g., N0 2 , NH 2 , halogen (as disclosed in, e.g., U.S. Patent 5,552,156) or a short alkane containing these groups.
  • R 3 is typically H or a short alkyl such as C 2 H 5 .
  • R 4 is typically H but may be other groups, e.g., a methylenedioxy group with R-i .
  • exemplary camptothecin compounds include topotecan, irinotecan (CPT-11 ), 9-aminocamptothecin, 21 -lactam-20(S)-camptothecin, 10,11-methyIenedioxycamptothecin, SN-38, 9-nitrocamptothecin, 10- hydroxycamptothecin.
  • Exemplary compounds have the structures:
  • Camptothecin H H H Topotecan: OH (CH 3 ) 2 NHCH 2 H SN-38: OH H C 2 H 5 X: O for most analogs, NH for 21-lactam analogs
  • Camptothecins have the five rings shown here.
  • the ring labeled E must be intact (the lactone rather than carboxylate form) for maximum activity and minimum toxicity.
  • These compounds are useful to as cell cycle inhibitors, where they can function as topoisomerase I inhibitors and/or DNA cleavage agents. They have been shown useful in the treatment of proliferative disorders, including, for example, NSC lung; small cell lung; and cervical cancers.
  • the cell cycle inhibitor is a podophyllotoxin, or a derivative or an analogue thereof.
  • Exemplary compounds of this type are etoposide or teniposide, which have the following structures:
  • These compounds are thought to function as cell cycle inhibitors by being topoisomerase II inhibitors and/or by DNA cleaving agents. They have been shown useful as antiproliferative agents in, e.g., small cell lung, prostate, and brain cancers, and in retinoblastoma.
  • DNA topoisomerase inhibitor is lurtotecan dihydrochloride (11 H-1 ,4-dioxino[2,3-g]pyrano[3',4':6,7]indolizino[1 ,2- b]quinoline-9,12(8H,14H)-dione, 8-ethyl-2,3-dihydro-8-hydroxy-15-[(4-methyl-1- piperazinyl)methyl]-, dihydrochloride, (S)-).
  • the cell cycle inhibitor is an anthracycline.
  • Anthracyclines have the following general structure, where the R groups may be a variety of organic groups:
  • R groups are: Ri is CH 3 or CH 2 OH; R 2 is daunosamine or H; R 3 and R 4 are independently one of OH, N0 2 , NH 2 , F, Cl, Br, I, CN, H or groups derived from these; R 5-7 are all H or R 5 and R 6 are H and R 7 and R 8 are alkyl or halogen, or vice versa: R 7 and Re are H and R 5 and Re are alkyl or halogen. According to U.S. Patent 5,843,903, R 2 may be a conjugated peptide. According to U.S. Patent Nos.
  • R 5 may be OH or an ether linked alkyl group.
  • Ri may also be linked to the anthracycline ring by a group other than C(O), such as an alkyl or branched alkyl group having the C(O) linking moiety at its end, such as -CH 2 CH(CH 2 -X)C(0)-R 1 , wherein X is H or an alkyl group (see, e.g., U.S. Patent 4,215,062).
  • R 3 may have the following structure:
  • R 10 may be H or form a secondary amine with a group such as an aromatic group, saturated or partially saturated 5 or 6 membered heterocyclic having at least one ring nitrogen (see U.S. Patent 5,843,903). Alternately, R 10 may be derived from an amino acid, having the structure -
  • R 12 may be H, alkyl, aminoalkyl, amino, hydroxy, mercapto, phenyl, benzyl or methylthio (see U.S. Patent 4,296,105).
  • exemplary anthracyclines are doxorubicin, daunorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, and carubicin. Suitable compounds have the structures:
  • anthracyclines are anthramycin, mitoxantrone, menogaril, nogalamycin, aclacinomycin A, olivomycin A, chromomycin A 3 , and plicamycin having the structures:
  • the cell cycle inhibitor is a platinum compound.
  • suitable platinum complexes may be of Pt(ll) or Pt(IV) and have this basic structure:
  • X and Y are anionic leaving groups such as sulfate, phosphate, carboxylate, and halogen; Ri and R 2 are alkyl, amine, amino alkyl any may be further substituted, and are basically inert or bridging groups.
  • Pt(ll) complexes Zi and Z 2 are non-existent.
  • Pt(IV) Zi and Z 2 may be anionic groups such as halogen, hydroxy, carboxylate, ester, sulfate or phosphate. See, e.g., U.S. Patent Nos. 4,588,831 and 4,250,189.
  • Suitable platinum complexes may contain multiple Pt atoms. See, e.g., U.S. Patent Nos. 5,409,915 and 5,380,897.
  • platinum compounds are cisplatin, carboplatin, oxaliplatin, and miboplatin having the structures:
  • Oxaliplatin These compounds are thought to function as cell cycle inhibitors by binding to DNA, i.e., acting as alkylating agents of DNA. These compounds have been shown useful in the treatment of cell proliferative disorders, including, e.g., NSC lung; small cell lung; breast; cervical; brain; head and neck; esophageal; retinoblastom; liver; bile duct; bladder; penile; and vulvar cancers; and soft tissue sarcoma.
  • the cell cycle inhibitor is a nitrosourea. Nitrosourease have the following general structure (C5), where typical R groups are shown below.
  • R groups include cyclic alkanes, alkanes, halogen substituted groups, sugars, aryl and heteroaryl groups, phosphonyl and sulfonyl groups.
  • R may suitably be CH 2 - C(X)(Y)(Z), wherein X and Y may be the same or different members of the following groups: phenyl, cyclyhexyl, or a phenyl or cyclohexyl group substituted with groups such as halogen, lower alkyl (C-i- ), trifluore methyl, cyano, phenyl, cyclohexyl, lower alkyloxy (C- ⁇ -4 ).
  • Ri and R 2 may be the same or different members of the following group: lower alkyl (C ⁇ - ) and benzyl, or together Ri and R may form a saturated 5 or 6 membered heterocyclic such as pyrrolidine, piperidine, morfoline, thiomorfoline, N-lower alkyl piperazine, where the heterocyclic may be optionally substituted with lower alkyl groups.
  • R and R' of formula (C5) may be the same or different, where each may be a substituted or unsubstituted hydrocarbon having 1-10 carbons.
  • Substitutions may include hydrocarbyl, halo, ester, amide, carboxylic acid, ether, thioether and alcohol groups.
  • R of formula (C5) may be an amide bond and a pyranose structure (e.g., methyl 2'-(N-(N-(2-chloroethyl)- N-nitroso-carbamoyl)-glycyl)amino-2'-deoxy- ⁇ -D-glucopyranoside).
  • a pyranose structure e.g., methyl 2'-(N-(N-(2-chloroethyl)- N-nitroso-carbamoyl)-glycyl
  • R of formula (C5) may be an alkyl group of 2 to 6 carbons and may be substituted with an ester, sulfonyl, or hydroxyl group. It may also be substituted with a carboxylic acid or CONH 2 group.
  • exemplary nitrosoureas are BCNU (carmustine), methyl-CCNU (semustine), CCNU (lomustine), ranimustine, nimustine, chlorozotocin, fotemustine, and streptozocin, having the structures:
  • the cell cycle inhibitor is a nitroimidazole, where exemplary nitroimidazoles are metronidazole, benznidazole, etanidazole, and misonidazole, having the structures:
  • the cell cycle inhibitor is a folic acid antagonist, such as methotrexate or derivatives or analogues thereof, including edatrexate, trimetrexate, raltitrexed, piritrexim, denopterin, tomudex, and pteropterin.
  • Methotrexate analogues have the following general structure:
  • R group may be selected from organic groups, particularly those groups set forth in U.S. Patent Nos. 5,166,149 and 5,382,582.
  • R-i may be N
  • R 2 may be N or C(CH 3 )
  • R 3 and R 3 ' may H or alkyl, e.g., CH 3 , R 4 may be a single bond or NR, where R is H or alkyl group.
  • R 5 , 6 , 8 may be H, OCH 3 , or alternately they can be halogens or hydro groups.
  • R 7 is a side chain of the general structure:
  • the carboxyl groups in the side chain may be esterified or form a salt such as a Zn 2+ salt.
  • Rg and R 10 can be NH 2 or may be alkyl substituted.
  • Exemplary folic acid antagonist compounds have the structures:
  • the cell cycle inhibitor is a cytidine analogue, such as cytarabine or derivatives or analogues thereof, including enocitabine, FMdC ((E(-2'-deoxy-2'-(fluoromethylene)cytidine), gemcitabine, 5-azacitidine, ancitabine, and 6-azauridine.
  • cytidine analogue such as cytarabine or derivatives or analogues thereof, including enocitabine, FMdC ((E(-2'-deoxy-2'-(fluoromethylene)cytidine), gemcitabine, 5-azacitidine, ancitabine, and 6-azauridine.
  • Exemplary compounds have the structures:
  • the cell cycle inhibitor is a pyrimidine analogue.
  • the pyrimidine analogues have the general structure: wherein positions 2', 3' and 5' on the sugar ring (R 2 , R3 and R 4 , respectively) can be H, hydroxyl, phosphoryl (see, e.g., U.S. Patent 4,086,417) or ester (see, e.g., U.S. Patent 3,894,000).
  • Esters can be of alkyl, cycloalkyl, aryl or heterocyclo/aryl types.
  • the 2' carbon can be hydroxylated at either R 2 or R 2 ', the other group is H.
  • the 2' carbon can be substituted with halogens e.g., fluoro or difluoro cytidines such as Gemcytabine.
  • the sugar can be substituted for another heterocyclic group such as a furyl group or for an alkane, an alkyl ether or an amide linked alkane such as C(0)NH(CH 2 ) CH 3 .
  • the 2° amine can be substituted with an aliphatic acyl (Ri) linked with an amide (see, e.g., U.S. Patent 3,991 ,045) or urethane (see, e.g., U.S. Patent 3,894,000) bond. It can also be further substituted to form a quaternary ammonium salt.
  • R 5 in the pyrimidine ring may be N or CR, where R is H, halogen containing groups, or alkyl (see, e.g., U.S. Patent No. 4,086,417).
  • R 8 is H or R 7 and Rs together can form a double bond or R 8 can be X, where X is:
  • the cell cycle inhibitor is a fluoropyrimidine analogue, such as 5-fluorouracil, or an analogue or derivative thereof, including carmofur, doxifluridine, emitefur, tegafur, and floxuridine.
  • fluoropyrimidine analogue such as 5-fluorouracil
  • an analogue or derivative thereof including carmofur, doxifluridine, emitefur, tegafur, and floxuridine.
  • Exemplary compounds have the structures:
  • fluoropyrimidine analogues include 5-FudR (5- fluoro-deoxyuridine), or an analogue or derivative thereof, including 5- iododeoxyuridine (5-ludR), 5-bromodeoxyuridine (5-BudR), fluorouridine triphosphate (5-FUTP), and fluorodeoxyuridine monophosphate (5-dFUMP).
  • 5-FudR 5- fluoro-deoxyuridine
  • an analogue or derivative thereof including 5- iododeoxyuridine (5-ludR), 5-bromodeoxyuridine (5-BudR), fluorouridine triphosphate (5-FUTP), and fluorodeoxyuridine monophosphate (5-dFUMP).
  • Exemplary compounds have the structures:
  • the cell cycle inhibitor is a purine analogue.
  • Purine analogues have the following general structure.
  • N signifies nitrogen and V, W, X, Z can be either carbon or nitrogen with the following provisos.
  • Ring A may have 0 to 3 nitrogen atoms in its structure. If two nitrogens are present in ring A, one must be in the W position. If only one is present, it must not be in the Q position. V and Q must not be simultaneously nitrogen. Z and Q must not be simultaneously nitrogen. If Z is nitrogen, R 3 is not present.
  • R ⁇ -3 are independently one of H, halogen, C ⁇ -7 alkyl, C ⁇ -7 alkenyl, hydroxyl, mercapto, C ⁇ -7 alkylthio, C ⁇ -7 alkoxy, C- 2 - 7 alkenyloxy, aryl oxy, nitro, primary, secondary or tertiary amine containing group.
  • R 5-8 are H or up to two of the positions may contain independently one of OH, halogen, cyano, azido, substituted amino, R 5 and R 7 can together form a double bond.
  • Y is H, a C-i- alkylcarbonyl, or a mono- di or tri phosphate.
  • Exemplary suitable purine analogues include 6-mercaptopurine, thiguanosine, thiamiprine, cladribine, fludaribine, tubercidin, puromycin, pentoxyfilline; where these compounds may optionally be phosphorylated.
  • Exemplary compounds have the structures: 6-Mercaptopur ⁇ ne
  • the cell cycle inhibitor is a nitrogen mustard.
  • suitable nitrogen mustards are known and are suitably used as a cell cycle inhibitor in the present invention.
  • Suitable nitrogen mustards are also known as cyclophosphamides.
  • a preferred nitrogen mustard has the general structure:
  • alkane typically CH 2 CH(CH 3 )CI, or a polycyclic group such as B, or a substituted phenyl such as C or a heterocyclic group such as D.
  • R1-2 are H or CH 2 CH 2 CI;
  • R 3 is H or oxygen-containing groups such as hydroperoxy; and
  • R ⁇ can be alkyl, aryl, heterocyclic.
  • the cyclic moiety need not be intact. See, e.g., U.S. Patent Nos. 5,472,956, 4,908,356, 4,841 ,085 that describe the following type of structure:
  • Ri is H or CH2CH 2 CI
  • R 2-6 are various substituent groups.
  • Exemplary nitrogen mustards include methylchloroethamine, and analogues or derivatives thereof, including methylchloroethamine oxide hydrohchloride, novembichin, and mannomustine (a halogenated sugar).
  • Exemplary compounds have the structures:
  • the nitrogen mustard may be cyclophosphamide, ifosfamide, perfosfamide, or torofosfamide, where these compounds have the structures: , R, Cyclophosphamide H ( H 2 CH 2 CI H Ifosfamide CH 2 CH 2 CI H H Perfosfamide CH 2 CH 2 CI H OOH Torofosfamide CH 2 CH 2 CI CH 2 CH 2 CI H
  • the nitrogen mustard may be estramustine, or an analogue or derivative thereof, including phenesterine, prednimustine, and estramustine P0 .
  • suitable nitrogen mustard type cell cycle inhibitors of the present invention have the structures:
  • the nitrogen mustard may be chlorambucil, or an analogue or derivative thereof, including melphalan and chlormaphazine.
  • suitable nitrogen mustard type cell cycle inhibitors of the present invention have the structures:
  • Chlornaphazine H together forms a benzene ring
  • the nitrogen mustard may be uracil mustard, which has the structure:
  • the nitrogen mustards are thought to function as cell cycle inhibitors by serving as alkylating agents for DNA.
  • Nitrogen mustards have been shown useful in the treatment of cell proliferative disorders including, for example, small cell lung, breast, cervical, head and neck, prostate, retinoblastoma, and soft tissue sarcoma.
  • the cell cycle inhibitor of the present invention may be a hydroxyurea. Hydroxyureas have the following general structure:
  • Suitable hydroxyureas are disclosed in, for example, U.S. Patent No. 6,080,874, wherein R ⁇ is:
  • R 2 is an alkyl group having 1-4 carbons and R 3 is one of H, acyl, methyl, ethyl, and mixtures thereof, such as a methylether.
  • R 3 is one of H, acyl, methyl, ethyl, and mixtures thereof, such as a methylether.
  • Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent No. 5,665,768, wherein Ri is a cycloalkenyl group, for example N-(3-(5-(4- fluorophenylthio)-furyl)-2-cyclopenten-1-yl)N-hydroxyurea; R 2 is H or an alkyl group having 1 to 4 carbons and R 3 is H; X is H or a cation.
  • Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent No.
  • Ri is a phenyl group substituted with on or more fluorine atoms
  • R 2 is a cyclopropyl group
  • R 3 and X is H.
  • Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent No. 5,066,658, wherein R 2 and R 3 together with the adjacent nitrogen form:
  • hydroxy urea has the structure:
  • Hydroxyureas are thought to function as cell cycle inhibitors by serving to inhibit DNA synthesis.
  • the cell cycle inhibitor is a mytomicin, such as mitomycin C, or an analogue or derivative thereof, such as porphyromycin.
  • Exemplary compounds have the structures: R Mitomycin C H Porphyromycin CH 3 (N-methyl Mitomycin C)
  • the cell cycle inhibitor is an alkyl sulfonate, such as busulfan, or an analogue or derivative thereof, such as treosulfan, improsulfan, piposulfan, and pipobroman.
  • alkyl sulfonate such as busulfan
  • an analogue or derivative thereof such as treosulfan, improsulfan, piposulfan, and pipobroman.
  • Exemplary compounds have the structures:
  • the cell cycle inhibitor is a benzamide.
  • the cell cycle inhibitor is a nicotinamide.
  • X is either O or S; A is commonly NH 2 or it can be OH or an alkoxy group; B is N or C-R 4 , where P is H or an ether-linked hydroxylated alkane such as OCH 2 CH 2 OH, the alkane may be linear or branched and may contain one or more hydroxyl groups. Alternately, B may be N-R 5 in which case the double bond in the ring involving B is a single bond. R 5 may be H, and alkyl or an aryl group (see, e.g., U.S. Patent No.
  • R 2 is H, OR 6 , SR 6 or NHR 6 , where R 6 is an alkyl group; and R 3 is H, a lower alkyl, an ether linked lower alkyl such as -O-Me or -O-ethyl (see, e.g., U.S. Patent No. 5,215,738).
  • Suitable benzamide compounds have the structures:
  • the cell cycle inhibitor is a halogenated sugar, such as mitolactol, or an analogue or derivative thereof, including mitobronitol and mannomustine.
  • exemplary compounds have the structures:
  • the cell cycle inhibitor is a diazo compound, such as azaserine, or an analogue or derivative thereof, including 6-diazo-5- oxo-L-norleucine and 5-diazouracil (also a pyrimidine analog).
  • exemplary compounds have the structures: Azaserine o single bond 6-diazo-5-oxo- L-norleucine single bond CH 2
  • pazelliptine wortmannin; metoclopramide; RSU; buthionine sulfoxime; tumeric; curcumin; AG337, a thymidylate synthase inhibitor; levamisole; lentinan, a polysaccharide; razoxane, an EDTA analogue; indomethacin; chlorpromazine; ⁇ and ⁇ interferon; MnBOPP; gadolinium texaphyrin; 4-amino-1 ,8-naphthalimide; staurosporine derivative of CGP; and SR-2508.
  • the cell cycle inhibitor is a DNA alylating agent.
  • the cell cycle inhibitor is an anti-microtubule agent.
  • the cell cycle inhibitor is a topoisomerase inhibitor.
  • the cell cycle inhibitor is a DNA cleaving agent.
  • the cell cycle inhibitor is an antimetabolite.
  • the cell cycle inhibitor functions by inhibiting adenosine deaminase (e.g., as a purine analogue).
  • the cell cycle inhibitor functions by inhibiting purine ring synthesis and/or as a nucleotide interconversion inhibitor (e.g., as a purine analogue such as mercaptopurine).
  • the cell cycle inhibitor functions by inhibiting dihydrofolate reduction and/or as a thymidine monophosphate block (e.g., methotrexate). In another aspect, the cell cycle inhibitor functions by causing DNA damage (e.g., bleomycin).
  • a thymidine monophosphate block e.g., methotrexate
  • the cell cycle inhibitor functions by causing DNA damage (e.g., bleomycin).
  • the cell cycle inhibitor functions as a DNA intercalation agent and/or RNA synthesis inhibition (e.g., doxorubicin, aclarubicin, or detorubicin (acetic acid, diethoxy-, 2-[4-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]- 1 ,2,3,4,6,11-hexahydro-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-2- naphthacenyl]-2-oxoethyl ester, (2S-cis)-)).
  • doxorubicin e.g., doxorubicin, aclarubicin, or detorubicin (acetic acid, diethoxy-, 2-[4-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]- 1 ,2,3,
  • the cell cycle inhibitor functions by inhibiting pyrimidine synthesis (e.g., N-phosphonoacetyl-L- aspartate). In another aspect, the cell cycle inhibitor functions by inhibiting ribonucleotides (e.g., hydroxyurea). In another aspect, the cell cycle inhibitor functions by inhibiting thymidine monophosphate (e.g., 5-fluorouracil). In another aspect, the cell cycle inhibitor functions by inhibiting DNA synthesis (e.g., cytarabine). In another aspect, the cell cycle inhibitor functions by causing DNA adduct formation (e.g., platinum compounds). In another aspect, the cell cycle inhibitor functions by inhibiting protein synthesis (e.g., L- asparginase).
  • pyrimidine synthesis e.g., N-phosphonoacetyl-L- aspartate
  • the cell cycle inhibitor functions by inhibiting ribonucleotides (e.g., hydroxyurea).
  • the cell cycle inhibitor functions by inhibiting th
  • the cell cycle inhibitor functions by inhibiting microtubule function (e.g., taxanes).
  • the cell cycle inhibitor acts at one or more of the steps in the biological pathway shown in Figure 1. Additional cell cycle inhibitor s useful in the present invention, as well as a discussion of the mechanisms of action, may be found in Hardman J.G., Limbird L.E. Molinoff R.B., Ruddon R W., Gilman A.G. editors, Chemotherapy of Neoplastic Diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics Ninth Edition, McGraw-Hill Health Professions Division, New York, 1996, pages 1225-1287. See also U.S. Patent Nos.
  • the cell-cycle inhibitor is camptothecin, mitoxantrone, etoposide, 5-fluorouracil, doxorubicin, methotrexate, peloruside A, mitomycin C, or a CDK-2 inhibitor or an analogue or derivative of any member of the class of listed compounds.
  • the cell-cycle inhibitor is HT1-286, plicamycin; or mithramycin, or an analogue or derivative thereof.
  • cell cycle inhibitors also include, e.g., 7- hexanoyltaxol (QP-2), cytochalasin A, lantrunculin D, actinomycin-D, Ro-31- 7453 (3-(6-nitro-1-methyl-3-indolyl)-4-(1-methyl-3-indolyl)pyrrole-2,5-dione), PNU-151807, brostallicin, C2-ceramide, cytarabine ocfosfate (2(1 H)- pyrimidinone, 4-amino-1-(5-0-(hydroxy(octadecyloxy)phosphinyl)- ⁇ -D- arabinofuranosyl)-, monosodium salt), paclitaxel (5 ⁇ ,20-epoxy-1 ,2 alpha,4,7 ⁇ , 10 ⁇ , 13 alpha-hexahydroxytax-11 -en-9-one-4, 10-diacetate-2- benzoate-13-(alpha
  • the pharmacologically active compound is a cyclin dependent protein kinase inhibitor (e.g., R-roscovitine, CYC-101 , CYC-103, CYC-400, MX-7065, alvocidib (4H-1-Benzopyran-4-one, 2-(2- chlorophenyl)-5,7-dihydroxy-8-(3-hydroxy-1-methyl-4-piperidinyl)-, cis-(-)-), SU- 9516, AG-12275, PD-0166285, CGP-79807, fascaplysin, GW-8510 (benzenesulfonamide, 4-((Z)-(6,7-dihydro-7-oxo-8H-pyrrolo(2,3- g)benzothiazol-8-ylidene)methyl)amino)-N-(3-hydroxy-2,2-dimethylpropyl)-), GW
  • the pharmacologically active compound is an EGF (epidermal growth factor) kinase inhibitor (e.g., erlotinib (4- quinazolinamine, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-, monohydrochloride), erbstatin, BIBX-1382, gefitinib (4-quinazolinamine, N-(3- chloro-4-fluorophenyl)-7-methoxy-6-(3-(4-morpholinyl)propoxy)), or an analogue or derivative thereof).
  • EGF epidermatiti factor
  • the pharmacologically active compound is an elastase inhibitor (e.g., ONO-6818, sivelestat sodium hydrate (glycine, N- (2-(((4-(2,2-dimethyl-1-oxopropoxy)phenyl)sulfonyl)amino)benzoyl)-), erdosteine (acetic acid, ((2-oxo-2-((tetrahydro-2-oxo-3-thienyl)amino)ethyl)thio)- ), MDL-100948A, MDL-104238 (N-(4-(4-morpholinylcarbonyl)benzoyl)-L-valyl- N'-(3,3,4,4,4-pentafluoro-1 -(1 -methylethyl)-2-oxobutyl)-L-2-azetamide), MDL- 27324 (L-prolinamide, N- (2-((4-(2,2-di
  • the pharmacologically active compound is a factor Xa inhibitor (e.g., CY-222, fondaparinux sodium (alpha-D- glucopyranoside, methyl 0-2-deoxy-6-0-sulfo-2-(sulfoamino)-alpha-D- glucopyranosyI-(1-4)-0- ⁇ -D-glucopyranuronosyl-(1-4)-0-2-deoxy-3,6-di-0- sulfo-2-(sulfoamino)-alpha-D-glucopyranosyl-(1-4)-0-2-0-sulfo-alpha-L- idopyranuronosyl-(1-4)-2-deoxy-2-(sulfoamino)-, 6-(hydrogen sulfate)), danaparoid sodium, or an analogue or derivative thereof).
  • factor Xa inhibitor e.g., CY-222, fondaparinux sodium (alpha-D
  • the pharmacologically active compound is a farnesyltransferase inhibitor (e.g., dichlorobenzoprim (2,4-diamino-5-(4- (3,4-dichlorobenzylamino)-3-nitrophenyl)-6-ethylpyrimidine), B-581 , B-956 (N- (8(R)-amino-2(S)-benzyl-5(S)-isopropyl-9-sulfanyl-3(Z),6(E)-nonadienoyl)-L- methionine), OSI-754, perillyl alcohol (1-cyclohexene-1 -methanol, 4-(1- methylethenyl)-, RPR-114334, lonafarnib (1-piperidinecarboxamide, 4-(2-(4- ((11 R)-3,10-dibromo-8-chloro-6,11-
  • a farnesyltransferase inhibitor e.
  • the pharmacologically active compound is a fibrinogen antagonist (e.g., 2(S)-((p-toluenesulfonyl)amino)-3-(((5,6,7,8,- tetrahydro-4-oxo-5-(2-(piperidin-4-yl)ethyl)-4H-pyrazolo-(1 ,5-a)(1 ,4)diazepin-2- yl)carbonyl)-amino)propionic acid, streptokinase (kinase (enzyme-activating), strepto-), urokinase (kinase (enzyme-activating), uro-), plasminogen activator, pamiteplase, monteplase, heberkinase, anistreplase, alteplase, pro-urokinase, picotamide (1 ,3-benzenedi
  • fibrinogen antagonist e.g.,
  • the pharmacologically active compound is a guanylate cyclase stimulant (e.g., isosorbide-5-mononitrate (D-glucitol, 1 ,4:3,6-dianhydro-, 5-nitrate), or an analogue or derivative thereof).
  • a guanylate cyclase stimulant e.g., isosorbide-5-mononitrate (D-glucitol, 1 ,4:3,6-dianhydro-, 5-nitrate), or an analogue or derivative thereof.
  • the pharmacologically active compound is a heat shock protein 90 antagonist (e.g., geldanamycin; NSC-33050 (17- allylaminogeldanamycin), rifabutin (rifamycin XIV, 1',4-didehydro-1-deoxy-1 ,4- dihydro-5'-(2-methylpropyl)-1-oxo-), 17AAG, or an analogue or derivative thereof).
  • a heat shock protein 90 antagonist e.g., geldanamycin; NSC-33050 (17- allylaminogeldanamycin), rifabutin (rifamycin XIV, 1',4-didehydro-1-deoxy-1 ,4- dihydro-5'-(2-methylpropyl)-1-oxo-), 17AAG, or an analogue or derivative thereof.
  • the pharmacologically active compound is an HMGCoA reductase inhibitor (e.g., BCP-671 , BB-476, fluvastatin (6- heptenoic acid, 7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1 H-indol-2-yl)-3,5- dihydroxy-, monosodium salt, (R*,S*-(E))-( ⁇ )-), dalvastatin (2H-pyran-2-one, 6- (2-(2-(2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethyl-1-cyclohexen-1- yl)ethenyl)tetrahydro)-4-hydroxy-, (4alpha,6 ⁇ (E))-( +/-)-), glenvastatin (2H-pyran- 2-one, 6-(2-(4-(4-)-2-(2-(4-(4-)-1-(1-
  • the pharmacologically active compound is a hydroorotate dehydrogenase inhibitor (e.g., leflunomide (4- isoxazolecarboxamide, 5-methyl-N-(4-(trifluoromethyl)phenyl)-), laflunimus (2- propenamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(3-methyl- 4(trifluoromethyl)phenyl)-, (Z)-), or atovaquone (1 ,4-naphthalenedione, 2-[4-(4- chlorophenyl)cyclohexyl]-3-hydroxy-, trans-, or an analogue or derivative thereof).
  • a hydroorotate dehydrogenase inhibitor e.g., leflunomide (4- isoxazolecarboxamide, 5-methyl-N-(4-(trifluoromethyl)phenyl)-), laflunimus (2- propenamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(
  • the pharmacologically active compound is an IKK2 inhibitor (e.g., MLN-120B, SPC-839, or an analogue or derivative thereof).
  • an IKK2 inhibitor e.g., MLN-120B, SPC-839, or an analogue or derivative thereof.
  • the pharmacologically active compound is an IL-1 , ICE or an IRAK antagonist (e.g., E-5090 (2-propenoic acid, 3-(5- ethyl-4-hydroxy-3-methoxy-1 -naphthalenyl)-2-methyl-, (Z)-), CH-164, CH-172, CH-490, AMG-719, iguratimod (N-(3-(formylamino)-4-oxo-6-phenoxy-4H- chromen-7-yl) methanesulfonamide), AV94-88, pralnacasan (6H- pyridazino(1 ,2-a)(1 ,2)diazepine-1 -carboxamide, N-((2R,3S)-2-ethoxytetrahydro- 5-oxo-3-furanyl)octahydro-9-((1-isoquinoliny
  • E-5090 (2-propenoic acid, 3-(5-
  • the pharmacologically active compound is an IL-4 agonist (e.g., glatiramir acetate (L-glutamic acid, polymer with L- alanine, L-lysine and L-tyrosine, acetate (salt)), or an analogue or derivative thereof).
  • an IL-4 agonist e.g., glatiramir acetate (L-glutamic acid, polymer with L- alanine, L-lysine and L-tyrosine, acetate (salt)
  • an analogue or derivative thereof e.g., glatiramir acetate (L-glutamic acid, polymer with L- alanine, L-lysine and L-tyrosine, acetate (salt)
  • the pharmacologically active compound is an immunomodulatory agent (e.g., biolimus, ABT-578, methylsulfamic acid 3- (2-methoxyphenoxy)-2-(((methylamino)sulfonyl)oxy)propyl ester, sirolimus (also referred to as rapamycin or RAPAMUNE (American Home Products, Inc., Madison, NJ)), CCI-779 (rapamycin 42-(3-hydroxy-2-(hydroxymethyl)-2- methylpropanoate)), LF-15-0195, NPC15669 (L-leucine, N-(((2,7-dimethyl-9H- fluoren-9-yl)methoxy)carbonyl)-), NPC-15670 (L-leucine, N-(((4,5-dimethyl-9H- fluoren-9-yl)methoxy)carbonyl)-), NPC-16570 (4-(2-(fluoren-9-yl)e
  • an immunomodulatory agent e.g
  • analogues of rapamycin include tacrolimus and derivatives thereof (e.g., EP0184162B1 and U.S. Patent No. 6,258,823) everolimus and derivatives thereof (e.g., U.S. Patent No.
  • sirolimus analogues and derivatives can be found in PCT Publication Nos. WO 97/10502, WO 96/41807, WO 96/35423, WO 96/03430, WO 96/00282, WO 95/16691 , WO 95/15328, WO 95/07468, WO 95/04738, WO 95/04060, WO 94/25022, WO 94/21644, WO 94/18207, WO 94/10843, WO 94/09010, WO 94/04540, WO 94/02485, WO 94/02137, WO 94/02136, WO 93/25533, WO 93/18043, WO 93/13663, WO 93/11130, WO 93/10122, WO 93/04680, WO 92/14737, and WO 92/05179.
  • sirolimus analogues and derivatives include tacrolimus and derivatives thereof (e.g., EP0184162B1 and U.S. Patent No. 6,258,823) everolimus and derivatives thereof (e.g., US Patent No. 5,665,772).
  • Further representative examples of sirolimus analogues and derivatives include ABT- 578 and others may be found in PCT Publication Nos.
  • WO 97/10502 WO 96/41807, WO 96/35423, WO 96/03430, WO 9600282, WO 95/16691 , WO 9515328, WO 95/07468, WO 95/04738, WO 95/04060, WO 94/25022, WO 94/21644, WO 94/18207, WO 94/10843, WO 94/09010, WO 94/04540, WO 94/02485, WO 94/02137, WO 94/02136, WO 93/25533, WO 93/18043, WO 93/13663, WO 93/11130, WO 93/10122, WO 93/04680, WO 92/14737, and WO 92/05179.
  • U.S. patents include U.S. Patent Nos. 6,342,507; 5,985,890; 5,604,234; 5,597,715; 5,583,139; 5,563,172; 5,561 ,228; 5,561 ,137 5,541 ,193; 5,541 ,189; 5,534,632; 5,527,907; 5,484,799; 5,457,194; 5,457,182 5,362,735; 5,324,644; 5,318,895; 5,310,903; 5,310,901 ; 5,258,389; 5,252,732 5,247,076; 5,225,403; 5,221 ,625; 5,210,030; 5,208,241 , 5,200,411 ; 5,198,421 5,147,877; 5,140,018; 5,116,756; 5,109,112; 5,093,338; and 5,091 ,389.
  • the fibrosis-inhibiting agent may be, e.g., rapamycin (sirolimus), everolimus, biolimus, tresperimus, auranofin, 27-0- demethylrapamycin, tacrolimus, gusperimus, pimecrolimus, or ABT-578.
  • the pharmacologically active compound is an inosine monophosphate dehydrogenase (IMPDH) inhibitor (e.g., mycophenolic acid, mycophenolate mofetil (4-hexenoic acid, 6-(1 ,3-dihydro-4- hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-, 2-(4- morpholinyl)ethyl ester, (E)-), ribavirin (1 H-1 ,2,4-triazole-3-carboxamide, 1- ⁇ -D- ribofuranosyl-), tiazofurin (4-thiazolecarboxamide, 2- ⁇ -D-ribofuranosyl-), viramidine, aminothiadiazole, thiophenfurin, tiazofurin) or an analogue or derivative thereof.
  • IMPDH inosine monophosphate dehydrogenase
  • the pharmacologically active compound is a leukotreine inhibitor (e.g., ONO-4057(benzenepropanoic acid, 2-(4- carboxybutoxy)-6-((6-(4-methoxyphenyl)-5-hexenyl)oxy)-, (E)-), ONO-LB-448, pirodomast 1 ,8-naphthyridin-2(1 H)-one, 4-hydroxy-1-phenyl-3-(1-pyrrolidinyl)-, Sch-40120 (benzo(b)(1 ,8)naphthyridin-5(7H)-one, 10-(3-chlorophenyl)-6,8,9,10- tetrahydro-), L-656224 (4-benzofuranol, 7-chloro-2-((4-methoxyphenyl)methyl)- 3-methyl-5-propyl-), MAFP (methyl arachidon),
  • the pharmacologically active compound is a MCP-1 antagonist (e.g., nitronaproxen (2-napthaleneacetic acid, 6- methoxy-alpha-methyl 4-(nitrooxy)butyl ester (alpha S)-), bindarit (2-(1 ⁇ benzylindazol-3-ylmethoxy)-2-methylpropanoic acid), 1-alpha-25 dihydroxy vitamin D 3, or an analogue or derivative thereof).
  • MCP-1 antagonist e.g., nitronaproxen (2-napthaleneacetic acid, 6- methoxy-alpha-methyl 4-(nitrooxy)butyl ester (alpha S)-), bindarit (2-(1 ⁇ benzylindazol-3-ylmethoxy)-2-methylpropanoic acid), 1-alpha-25 dihydroxy vitamin D 3, or an analogue or derivative thereof).
  • the pharmacologically active compound is a matrix metalloproteinase (MMP) inhibitor (e.g., D-9120, doxycycline (2- naphthacenecarboxamide, 4-(dimethylamino)-1 ,4,4a, 5, 5a, 6,11 ,12a-octahydro- 3,5,10,12,12a-pentahydroxy-6-methyl-1 ,11-dioxo- (4S-(4 alpha, 4a alpha, 5 Ipha, 5a alpha, 6 alpha, 12a alpha))-), BB-2827, BB-1101 (2S-allyl-N1-hydroxy- 3R-isobutyl-N4-(1S-methylcarbamoyl-2-phenylethyl)-succinamide), BB-2983, solimastat (N'-(2,2-dimethyl-1(S)-(N-(2-pyridyl)carbam
  • MMP matrix metalloproteina
  • the pharmacologically active compound is a NF kappa B (NFKB) inhibitor (e.g., AVE-0545, Oxi-104 (benzamide, 4- amino-3-chloro-N-(2-(diethylamino)ethyl)-), dexlipotam, R-flurbiprofen ((1 ,1'- biphenyl)-4-acetic acid, 2-fluoro-alpha-methyl), SP100030 (2-chloro-N-(3,5- di(trifluoromethyl)phenyl)-4-(trifluoromethyl)pyrimidine-5-carboxamide), AVE- 0545, Viatris, AVE-0547, Bay 11-7082, Bay 11-7085, 15 deoxy-prostaylandin J2, bortezomib (boronic acid, ((1R)-3-methyl-1-(((2S)-1-oxo-3-phenyl)
  • NFKB NF kappa B
  • the pharmacologically active compound is a NO antagonist (e.g., NCX-4016 (benzoic acid, 2-(acetyloxy)-, 3- ((nitrooxy)methyl)phenyl ester, NCX-2216, L-arginine or an analogue or derivative thereof).
  • NO antagonist e.g., NCX-4016 (benzoic acid, 2-(acetyloxy)-, 3- ((nitrooxy)methyl)phenyl ester, NCX-2216, L-arginine or an analogue or derivative thereof.
  • the pharmacologically active compound is a p38 MAP kinase inhibitor (e.g., GW-2286, CGP-52411, BIRB-798,
  • SB220025 RO-320-1195, RWJ-67657, RWJ-68354, SCIO-469, SCIO-323, AMG-548, CMC-146, SD-31145, CC-8866, Ro-320-1195, PD-98059 (4H-1- benzopyran-4-one, 2-(2-amino-3-methoxyphenyl)-), CGH-2466, doramapimod, SB-203580 (pyridine, 4-(5-(4-fluorophenyl)-2-(4-(methylsulfinyl)phenyl)-1 H- imidazol-4-yl)-), SB-220025 ((5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4- piperidinyl)imidazole), SB-281832, PD169316, SB202190, GSK-681323, EO- 1606, GSK-681323, or an analogue or derivative thereof).
  • WO 00/63204A2 WO 01/21591 A1 ; WO 01/35959A1 ; WO 01/74811A2; WO 02/18379A2; WO 2064594A2; WO 2083622A2; WO 2094842A2; WO 2096426A1 ; WO 2101015A2; WO 2103000A2; WO 3008413A1 ; WO 3016248A2; WO 3020715A1 ; WO 3024899A2; WO 3031431 A1 ; WO3040103A1 ; WO 3053940A1 ; WO 3053941 A2; WO 3063799A2; WO 3079986A2; WO 3080024A2; WO 3082287A1 ; WO 97/44467A1 ; WO 99/01449A1 ; and WO 99/58523A1.
  • the pharmacologically active compound is a phosphodiesterase inhibitor (e.g., CDP-840 (pyridine, 4-((2R)-2-(3- (cyclopentyloxy)-4-methoxyphenyl)-2-phenylethyl)-), CH-3697, CT-2820, D- 22888 (imidazo(1 ,5-a)pyrido(3,2-e)pyrazin-6(5H)-one, 9-ethyl-2-methoxy-7- methyl-5-propyl-), D-4418 (8-methoxyquinoline-5-(N-(2,5-dichloropyridin-3- yl))carboxamide), 1 -(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-dichloro-4- pyridyl) ethanone oxime, D-4396, ONO-6126, CDC-998,
  • CDP-840 pyridine, 4-((2R
  • phosphodiesterase inhibitors include denbufylline (1 H-purine-2,6-dione, 1 ,3-dibutyl-3,7-dihydro-7-(2-oxopropyl)-), propentofylline (1 H-purine-2,6-dione, 3,7-dihydro-3-methyl-1-(5-oxohexyl)-7- propyl-) and pelrinone (5-pyrimidinecarbonitrile, 1 ,4-dihydro-2-methyl-4-oxo-6- [(3-pyridinylmethyl)amino]-).
  • phosphodiesterase III inhibitors include enoximone (2H-imidazol-2-one, 1 ,3-dihydro-4-methyl-5-[4-(methylthio)benzoyl]- ), and saterinone (3-pyridinecarbonitrile, 1 ,2-dihydro-5-[4-[2-hydroxy-3-[4-(2- methoxyphenyl)-1-piperazinyl]propoxy]phenyl]-6-methyl-2-oxo-).
  • phosphodiesterase IV inhibitors include AWD- 12-281 , 3-auinolinecarboxylic acid, 1-ethyl-6-fluoro-1 ,4-dihydro-7-(4-methyl-1- piperazinyl)-4-oxo-), tadalafil (pyrazino(1 ',2':1 ,6)pyrido(3,4-b)indoIe1 ,4-dione, 6- (1 ,3-benzodioxol-5-yl)-2,3,6,7,12,12a-he ⁇ ahydro-2-methyl-, (6R-trans)), and filaminast (ethanone, 1-[3-(cyclopentyloxy)-4-methoxyphenyI]-, O- (aminocarbonyl)oxime, (1 E)-)
  • Another example of a phosphodiesterase V inhibitor is vardenafil (piperazine, 1-(3-(1 ,4-dihydro
  • TGF beta Inhibitors in another embodiment, is a TGF beta Inhibitor (e.g., mannose-6-phosphate, LF-984, tamoxifen (ethanamine, 2-(4-(1 ,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl-, (Z)-), tranilast, or an analogue or derivative thereof).
  • TGF beta Inhibitor e.g., mannose-6-phosphate, LF-984, tamoxifen (ethanamine, 2-(4-(1 ,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl-, (Z)-), tranilast, or an analogue or derivative thereof.
  • the pharmacologically active compound is a thromboxane A2 antagonist (e.g., CGS-22652 (3-pyridineheptanoic acid, y- (4-(((4-chlorophenyl)sulfonyl)amino)butyl)-, (.+-.)-), ozagrel (2-propenoic acid, 3- (4-(1 H-imidazol-1-ylmethyl)phenyl)-, (E)-), argatroban (2-piperidinecarboxylic acid, 1 -(5-((aminoiminomethyl)amino)-1 -oxo-2-(((1 ,2,3,4-tetrahydro-3-methyl-8- quinolinyl)sulfonyl)amino)pentyl)-4-methyl-), ramatroban (9H-carbazole-9- propanoic acid, 3-(((4-fluorine), aminoe-2-, ((4-
  • the pharmacologically active compound is a tyrosine kinase inhibitor (e.g., SKI-606, ER-068224, SD-208, N-(6- benzothiazolyl)-4-(2-(1-piperazinyl)pyrid-5-yl)-2-pyrimidineamine, celastrol (24,25,26-trinoroleana-1(10),3,5,7-tetraen-29-oic acid, 3-hydroxy-9,13-dimethyl- 2-oxo-, (9 beta.,13alpha,14 ⁇ ,20 alpha)-), CP-127374 (geldanamycin, 17- demethoxy-17-(2-propenylamino)-), CP-564959, PD-171026, CGP-52411 (1 H- lsoindole-1 ,3(2H)-dione, 4,5-bis(phenylamino)-), CGP-5
  • CGP-52411 (1 H- lsoin
  • the pharmacologically active compound is a fibroblast growth factor inhibitor (e.g., CT-052923 (((2H-benzo(d)1 ,3- dioxalan-5-methyl)amino)(4-(6,7-dimethoxyquinazolin-4-yl)piperazinyl)methane- 1-thione), or an analogue or derivative thereof).
  • a fibroblast growth factor inhibitor e.g., CT-052923 (((2H-benzo(d)1 ,3- dioxalan-5-methyl)amino)(4-(6,7-dimethoxyquinazolin-4-yl)piperazinyl)methane- 1-thione
  • the pharmacologically active compound is a protein kinase inhibitor (e.g., KP-0201448, NPC15437 (hexanamide, 2,6- diamino-N-((1-(1-oxotridecyl)-2-piperidinyl)methyl)-), fasudil (1 H-1 ,4-diazepine, hexahydro-1-(5-isoquinolinylsulfonyl)-), midostaurin (benzamide, N- (2,3, 10,11 ,12,13-hexahydro-10-methoxy-9-methyl-1 -oxo-9, 13-epoxy-1 H,9H- diindolo(1 ,2,3-gh:3',2',1'-lm)pyrrolo(3,4-j)(1 ,7)benzodiazonin-11-yl)-N-methyl-, (9Aipha),
  • the pharmacologically active compound is a PDGF receptor kinase inhibitor (e.g., RPR-127963E, or an analogue or derivative thereof).
  • the pharmacologically active compound is an endothelial growth factor receptor kinase inhibitor (e.g., CEP-7055, SU- 0879 ((E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2- (aminothiocarbonyl)acrylonitrile), BIBF-1000, AG-013736 (CP-868596), AMG- 706, AVE-0005, NM-3 (3-(2-methylcarboxymethyl)-6-methoxy-8-hydroxy- isocoumarin), Bay-43-9006, SU-011248,or an analogue or derivative thereof).
  • endothelial growth factor receptor kinase inhibitor e.g., CEP-7055, SU- 0879 ((E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2- (aminothiocarbonyl)acrylonitrile), BIBF-1000, AG-013736 (CP-868596), AMG
  • the pharmacologically active compound is a retinoic acid receptor antagonist (e.g., etarotene (Ro-15-1570) (naphthalene, 6-(2-(4-(ethylsulfonyl)phenyl)-1 -methylethenyl)-1 ,2,3,4- tetrahydro-1 ,1 ,4,4-tetramethyl-, (E)-), (2E,4E)-3-methyl-5-(2-((E)-2-(2,6,6- trimethyl-1 -cyclohexen-1 -yl)ethenyl)-1 -cyclohexen-1 -yl)-2,4-pentadienoic acid, tocoretinate (retinoic acid, 3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12- trimethyltridecyl)-2H-1-benzopyran-6-yl este
  • retinoic acid receptor antagonist e.g., e
  • the pharmacologically active compound is a platelet derived growth factor receptor kinase inhibitor (e.g., leflunomide (4- isoxazolecarboxamide, 5-methyl-N-(4-(trifluoromethyl)phenyl)-, or an analogue or derivative thereof).
  • a platelet derived growth factor receptor kinase inhibitor e.g., leflunomide (4- isoxazolecarboxamide, 5-methyl-N-(4-(trifluoromethyl)phenyl)-, or an analogue or derivative thereof.
  • the pharmacologically active compound is a fibrinogin antagonist (e.g., picotamide (1 ,3-benzenedicarboxamide, 4- methoxy-N,N'-bis(3-pyridinylmethyl)-, or an analogue or derivative thereof).
  • a fibrinogin antagonist e.g., picotamide (1 ,3-benzenedicarboxamide, 4- methoxy-N,N'-bis(3-pyridinylmethyl)-, or an analogue or derivative thereof.
  • the pharmacologically'active compound is an antimycotic agent (e.g., miconazole, sulconizole, parthenolide, rosconitine, nystatin, isoconazole, fluconazole, ketoconasole, imidazole, itraconazole, terpinafine, elonazole, bifonazole, clotrimazole, conazole, terconazole (piperazine, 1-(4-((2-(2,4-dichlorophenyl)-2-(1 H-1 ,2,4-triazol-1-ylmethyl)-1 ,3- dioxolan-4-yl)methoxy)phenyl)-4-(1 -methylethyl)-, cis-), isoconazole (1-(2-(2-6- dichlorobenzyloxy)-2-(2-,4-dichlorophenyl)ethyl)), gris
  • the pharmacologically active compound is a bisphosphonate (e.g., clodronate, alendronate, pamidronate, zoledronate, or an analogue or derivative thereof).
  • the pharmacologically active compound is a phospholipase A1 inhibitor (e.g., ioteprednol etabonate (androsta-1 ,4- diene-17-carboxylic acid, 17-((ethoxycarbonyl)oxy)-11-hydroxy-3-oxo-, chloromethyl ester, (11 ⁇ ,17 alpha)-, or an analogue or derivative thereof).
  • a phospholipase A1 inhibitor e.g., ioteprednol etabonate (androsta-1 ,4- diene-17-carboxylic acid, 17-((ethoxycarbonyl)oxy)-11-hydroxy-3-oxo-, chloromethyl ester, (11 ⁇ ,17 alpha)-, or an analogue or derivative thereof.
  • the pharmacologically active compound is a histamine H1 , H2, or H3 receptor antagonist (e.g., ranitidine (1 ,1- ethenediamine, N-(2-(((5-((dimethylamino)methyl)-2-furanyl)methyl)thio)ethyl)- N'-methyl-2-nitro-), niperotidine (N-(2-((5-)
  • the pharmacologically active compound is a macrolide antibiotic (e.g., dirithromycin (erythromycin, 9-deoxo-11-deoxy- 9,11-(imino(2-(2-methoxyethoxy)ethylidene)oxy)-, (9S(R))-), flurithromycin ethylsuccinate (erythromycin, 8-fluoro-mono(ethyl butanedioate) (ester)-), erythromycin stinoprate (erythromycin, 2'-propanoate, compound with N-acetyl- L-cysteine (1 :1)), clarithromycin (erythromycin, 6-O-methyl-), azithromycin (9- deoxo-9a-aza-9a-methyl-9a-homoerythromycin-A), telithromycin (3-de((2,6- dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribo
  • a macrolide antibiotic e.
  • the pharmacologically active compound is a GPIIb Ilia receptor antagonist (e.g., tirofiban hydrochloride (L-tyrosine, N- (butylsulfonyl)-0-(4-(4-piperidinyl)butyl)-, monohydrochloride-), eptifibatide (L- cysteinamide, N6-(aminoiminomethyl)-N2-(3-mercapto-1-oxopropyl)-L- lysylglycyl-L-alpha-aspartyl-L-tryptophyl-L-prolyl-, cyclic(1->6)-disulfide), xemilofiban hydrochloride, or an analogue or derivative thereof).
  • a GPIIb Ilia receptor antagonist e.g., tirofiban hydrochloride (L-tyrosine, N- (butylsulfonyl)-0-(4-(4-
  • the pharmacologically active compound is an endothelin receptor antagonist (e.g., bosentan (benzenesulfonamide, 4- (1 ,1-dimethylethyl)-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)(2,2'- bipyrimidin)-4-yl)-, or an analogue or derivative thereof).
  • an endothelin receptor antagonist e.g., bosentan (benzenesulfonamide, 4- (1 ,1-dimethylethyl)-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)(2,2'- bipyrimidin)-4-yl
  • the pharmacologically active compound is a peroxisome proliferator-activated receptor agonist (e.g., gemfibrozil (pentanoic acid, 5-(2,5-dimethylphenoxy)-2,2-dimethyl-), fenofibrate (propanoic acid, 2-(4-(4-chlorobenzoyl)phenoxy)-2-methyl-, 1-methylethyl ester), ciprofibrate (propanoic acid, 2-(4-(2,2-dichlorocyclopropyl)phenoxy)-2-methyl-), rosiglitazone maleate (2,4-thiazolidinedione, 5-((4-(2-(methyl-2- pyridinylamino)ethoxy)phenyl)methyl)-, (Z)-2-butenedioate (1 :1)), pioglitazone hydrochloride (2,4-thiazolidine), 5-((4-(2-(methyl-2- pyridinylamino)e
  • the pharmacologically active compound is a peroxisome proliferator-activated receptor alpha agonist, such as GW-590735, GSK-677954, GSK501516, pioglitazone hydrochloride (2,4-thiazolidinedione, 5- [[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-, monohydrochloride (+/-)-, or an analogue or derivative thereof).
  • Estrogen Receptor Agents is an estrogen receptor agent (e.g., estradiol, 17- ⁇ -estradiol, or an analogue or derivative thereof).
  • the pharmacologically active compound is a somatostatin analogue (e.g., angiopeptin, or an analogue or derivative thereof).
  • the pharmacologically active compound is a neurokinin 1 antagonist (e.g., GW-597599, lanepitant ((1 ,4'-bipiperidine)-1'- acetamide, N-(2-(acetyl((2-methoxyphenyl)methyl)amino)-1 -(1 H-indol-3- ylmethyl)ethyl)- (R)-), nolpitantium chloride (1-azoniabicyclo[2.2.2]octane, 1-[2- [3-(3,4-dichlorophenyl)-1-[[3-(1-methylethoxy)phenyl]acetyl]-3-piperidinyl]ethyl]- 4-phenyl-, chloride, (S)-), or saredutant (benzamide, N-[4-[4-(acetylamino)-4- phenyl-1-piperidinyl
  • the pharmacologically active compound is a neurokinin 3 antagonist (e.g., talnetant (4-quinolinecarboxamide, 3- hydroxy-2-phenyl-N-[(1S)-1-phenylpropyl]-, or an analogue or derivative thereof).
  • talnetant 4-quinolinecarboxamide, 3- hydroxy-2-phenyl-N-[(1S)-1-phenylpropyl]-, or an analogue or derivative thereof.
  • the pharmacologically active compound is a neurokinin antagonist (e.g., GSK-679769, GSK-823296, SR-489686 (benzamide, N-[4-[4-(acetylamino)-4-phenyl-1-piperidinyl]-2-(3,4- dichlorophenyl)butyl]-N-methyl-, (S)-), SB-223412; SB-235375 (4- quinolinecarboxamide, 3-hydroxy-2-phenyl-N-[(1 S)-1 -phenylpropyl]-), UK- 226471 , or an analogue or derivative thereof).
  • a neurokinin antagonist e.g., GSK-679769, GSK-823296, SR-489686 (benzamide, N-[4-[4-(acetylamino)-4-phenyl-1-piperidinyl]-2-(3,4- dichlorophenyl)butyl]-N-methyl-, (S)
  • VLA-4 Antagonist in another embodiment, is a VLA-4 antagonist (e.g., GSK683699, or an analogue or derivative thereof).
  • the pharmacologically active compound is a osteoclast inhibitor (e.g., ibandronic acid (phosphonic acid, [1-hydroxy-3- (methylpentylamino)propylidene] bis-), alendronate sodium, or an analogue or derivative thereof).
  • a osteoclast inhibitor e.g., ibandronic acid (phosphonic acid, [1-hydroxy-3- (methylpentylamino)propylidene] bis-), alendronate sodium, or an analogue or derivative thereof.
  • the pharmacologically active compound is a DNA topoisomerase ATP hydrolysing inhibitor (e.g., enoxacin (1 ,8- naphthyridine-3-carboxylic acid, 1 -ethyl-6-f luoro-1 ,4-dihydro-4-oxo-7-(1- piperazinyl)-), levofloxacin (7H-Pyrido[1 ,2,3-de]-1 ,4-benzoxazine-6-carboxylic acid, 9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-, (S)-), ofloxacin (7H-pyrido[1 ,2,3-de]-1 ,4-benzoxazine-6-carboxylic acid, 9-fluoro-2,3- dihydro
  • enoxacin (1 ,8- naphthyridine-3-carboxylic
  • the pharmacologically active compound is an angiotensin I converting enzyme inhibitor (e.g., ramipril (cyclopenta[b]pyrrole-2-carboxylic acid, 1 -[2-[[1 -(ethoxycarbonyl)-3- phenylpropyl]amino]-1-oxopropyl]octahydro-, [2S-[1 [R*(R*)],2 alpha, 3a ⁇ , 6a ⁇ ]]- ), trandolapril (1H-indole-2-carboxylic acid, 1-[2-[(1-carboxy-3- phenylpropyl)amino]-1-oxopropyl]octahydro-, [2S-[1 [R*(R*)],2 alpha, 3a alpha,7a ⁇ ]]-), fasidotril (L) ramipril (cyclopenta[b]pyrrole-2-carbox
  • the pharmacologically active compound is an angiotensin II antagonist (e.g., HR-720 (1H-imidazole-5-carboxylic acid, 2- butyl-4-(methyIthio)-1-[[2 [[(propyIamino)carbonyl]amino]sulfonyl][1 ,1 '- biphenyl]-4-yl]methyl]-, dipotassium salt, or an analogue or derivative thereof).
  • an angiotensin II antagonist e.g., HR-720 (1H-imidazole-5-carboxylic acid, 2- butyl-4-(methyIthio)-1-[[2 [[(propyIamino)carbonyl]amino]sulfonyl][1 ,1 '- biphenyl]-4-yl]methyl]-, dipotassium salt, or an analogue or derivative thereof.
  • the pharmacologically active compound is an enkephalinase inhibitor (e.g., Aventis 100240 (pyrido[2,1- a][2]benzazepine-4-carboxylic acid, 7-[[2-(acetylthio)-1 -oxo-3- phenylpropyl]amino]-1 ,2,3,4,6,7,8,12b-octahydro-6-oxo-, [4S-[4 alpha, 7 alpha(R * ),12b ⁇ ]]-), AVE-7688, or an analogue or derivative thereof).
  • Aventis 100240 pyrido[2,1- a][2]benzazepine-4-carboxylic acid, 7-[[2-(acetylthio)-1 -oxo-3- phenylpropyl]amino]-1 ,2,3,4,6,7,8,12b-octahydro-6-oxo-, [4S-[
  • the pharmacologically active compound is peroxisome proliferator-activated receptor gamma agonist insulin sensitizer (e.g., rosiglitazone maleate (2,4-thiazolidinedione, 5-((4-(2-(methyl-2- pyridinylamino)ethoxy)phenyl)methyl)-, (Z)-2-butenedioate (1 :1 ), farglitazar (Gl- 262570, GW-2570, GW-3995, GW-5393, GW-9765), LY-929, LY-519818, LY- 674, or LSN-862), or an analogue or derivative thereof).
  • peroxisome proliferator-activated receptor gamma agonist insulin sensitizer e.g., rosiglitazone maleate (2,4-thiazolidinedione, 5-((4-(2-(methyl-2- pyridinylamino)ethoxy)phenyl)methyl)-
  • the pharmacologically active compound is a protein kinase C inhibitor, such as ruboxistaurin mesylate (9H.18H- 5,21 :12,17-dimethenodibenzo(e, k)pyrrolo(3,4- h)(1 ,4,13)oxadiazacyclohexadecine-18,20(19H)-dione,9- ((dimethylamino)methyl)-6,7,10,11-tetrahydro-, (S)-), safingol (1 ,3- octadecanediol, 2-amino-, [S-(R*,R*)]-), or enzastaurin hydrochloride (1H- pyrole-2,5-dione, 3-(1-methyl-1 H-indol-3-yl)-4-[1-[1-(2-pyridinylmethyl)-4-
  • ruboxistaurin mesylate 9H.18H
  • ROCK (rho-associated kinase) Inhibitors in another embodiment, is a ROCK (rho-associated kinase) inhibitor, such as Y-27632, HA-1077, H- 1152 and 4-1 -(aminoalkyl)-N-(4-pyridyl) cyclohexanecarboxamide or an analogue or derivative thereof.
  • ROCK rho-associated kinase
  • the pharmacologically active compound is a CXCR3 inhibitor such as T-487, T0906487 or analogue or derivative thereof.
  • the pharmacologically active compound is an Itk inhibitor such as BMS-509744 or an analogue or derivative thereof.
  • the pharmacologically active compound is a cytosolic phospholipase A -alpha inhibitor such as efipladib (PLA-902) or analogue or derivative thereof.
  • the pharmacologically active compound is a PPAR Agonist (e.g., Metabolex ((-)-benzeneacetic acid, 4-chloro-alpha-[3- (trifluoromethyl)-phenoxy]-, 2-(acetylamino)ethyl ester), balaglitazone (5-(4-(3- methyl-4-oxo-3,4-dihydro-quinazolin-2-yl-methoxy)-benzyl)-thiazolidine-2,4- dione), ciglitazone (2,4-thiazolidinedione, 5-[[4-[(1- methylcyclohexyl)methoxy]phenyl]methyl]-), DRF-10945, farglitazar, GSK- 677954, GW-409544, GW-501516, GW-590735, GW-590735, K-11 , KRP-101
  • a PPAR Agonist e
  • the pharmacologically active compound is an immunosuppressant (e.g., batebulast (cyclohexanecarboxylic acid, 4- [[(aminoiminomethyl)amino]methyl]-, 4-(1 ,1-dimethylethyl)phenyl ester, trans-), cyclomunine, exalamide (benzamide, 2-(hexyloxy)-), LYN-001 , CCI-779 (rapamycin 42-(3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate)), 1726; 1726-D; AVE-1726, or an analogue or derivative thereof).
  • an immunosuppressant e.g., batebulast (cyclohexanecarboxylic acid, 4- [[(aminoiminomethyl)amino]methyl]-, 4-(1 ,1-dimethylethyl)phenyl ester, trans-), cyclomunine, exalamide (benzamide, 2-(hexy
  • the pharmacologically active compound is an Erb inhibitor (e.g., canertinib dihydrochloride (N-[4-(3-(chloro-4-fluoro- phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide dihydrochloride), CP-724714, or an analogue or derivative thereof).
  • an Erb inhibitor e.g., canertinib dihydrochloride (N-[4-(3-(chloro-4-fluoro- phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide dihydrochloride), CP-724714, or an analogue or derivative thereof).
  • the pharmacologically active compound is an apoptosis agonist (e.g., CEFLATONIN (CGX-635) (from Chemgenex Therapeutics, Inc., Menlo Park, CA), CHML, LBH-589, metoclopramide (benzamide, 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxy-), patupilone (4,17-dioxabicycIo(14.1.0)heptadecane-5,9-dione, 7,11-dihydroxy- 8,8,10,12,16-pentamethyl-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl, (1 R,3S,7S,10R,11S,12S,16R)), AN-9; pivanex (butanoic acid, (2,2-dimethyl-1- oxopropoxy)methyl ester
  • the pharmacologically active compound is an lipocortin agonist (e.g., CGP-13774 (9Alpha-chloro-6Alpha-fluoro- 11 ⁇ , 17alpha-dihydroxy-16Alpha-methyl-3-oxo-1 ,4-androstadiene-17 ⁇ - carboxylic acid-methylester-17-propionate), or analogue or derivative thereof).
  • CGP-13774 (9Alpha-chloro-6Alpha-fluoro- 11 ⁇ , 17alpha-dihydroxy-16Alpha-methyl-3-oxo-1 ,4-androstadiene-17 ⁇ - carboxylic acid-methylester-17-propionate
  • VCAM-1 antagonist in another embodiment, is a VCAM-1 antagonist (e.g., DW-908e, or an analogue or derivative thereof).
  • the pharmacologically active compound is a collagen antagonist (e.g., E-5050 (Benzenepropanamide, 4-(2,6- dimethylheptyl)-N-(2-hydroxyethyt)- ⁇ -methyl-), lufironil (2,4- Pyridinedicarboxamide, N,N'-bis(2-methoxyethyl)-), or an analogue or derivative thereof).
  • E-5050 Benzenepropanamide, 4-(2,6- dimethylheptyl)-N-(2-hydroxyethyt)- ⁇ -methyl-
  • lufironil (2,4- Pyridinedicarboxamide, N,N'-bis(2-methoxyethyl)-
  • the pharmacologically active compound is an alpha 2 integrin antagonist (e.g., E-7820, or an analogue or derivative thereof).
  • the pharmacologically active compound is a TNF alpha inhibitor (e.g., ethyl pyruvate, Genz-29155, lentinan (Ajinomoto Co., Inc. (Japan)), linomide (3-quinolinecarboxamide, 1 ,2-dihydro-4-hydroxy- N,1-dimethyl-2-oxo-N-phenyl-), UR-1505, or an analogue or derivative thereof).
  • a TNF alpha inhibitor e.g., ethyl pyruvate, Genz-29155, lentinan (Ajinomoto Co., Inc. (Japan)
  • linomide 3-quinolinecarboxamide, 1 ,2-dihydro-4-hydroxy- N,1-dimethyl-2-oxo-N-phenyl-
  • the pharmacologically active compound is a nitric oxide inhibitor (e.g., guanidioethyldisulfide, or an analogue or derivative thereof).
  • a nitric oxide inhibitor e.g., guanidioethyldisulfide, or an analogue or derivative thereof.
  • the pharmacologically active compound is a cathepsin inhibitor (e.g., SB-462795 or an analogue or derivative thereof).
  • compositions may further include a compound which acts to have an inhibitory effect on pathological processes in or around the treatment site.
  • additional therapeutically active agents include, by way of example and not limitation, anti-thrombotic agents, anti-proliferative agents, anti-inflammatory agents, neoplastic agents, enzymes, receptor antagonists or agonists, hormones, antibiotics, antimicrobial agents, antibodies, cytokine inhibitors, IMPDH (inosine monophosplate dehydrogenase) inhibitors tyrosine kinase inhibitors, MMP inhibitors, p38 MAP kinase inhibitors, immunosuppressants, apoptosis antagonists, caspase inhibitors, and JNK inhibitors.
  • anti-thrombotic agents include, by way of example and not limitation, anti-thrombotic agents, anti-proliferative agents, anti- inflammatory agents, neoplastic agents, enzymes, receptor antagonists or agonists, hormones, antibiotics, antimicrobial agents, antibodies, cytokine inhibitors, IMPDH (inosine monophosplate dehydrogenase) inhibitors tyrosine
  • the present invention also provides for the combination of an electrical device (as well as compositions and methods for making electrical devices) that includes an anti-fibrosing agent and an anti- infective agent, which reduces the likelihood of infections.
  • Infection is a common complication of the implantation of foreign bodies such as, for example, medical devices.
  • Foreign materials provide an ideal site for micro- organisms to attach and colonize. It is also hypothesized that there is an impairment of host defenses to infection in the microenvironment surrounding a foreign material. These factors make medical implants particularly susceptible to infection and make eradication of such an infection difficult, if not impossible, in most cases.
  • the present invention provides agents (e.g., chemotherapeutic agents) that can be released from a composition, and which have potent antimicrobial activity at extremely low doses.
  • agents e.g., chemotherapeutic agents
  • a wide variety of anti-infective agents can be utilized in combination with the present compositions. Suitable anti-infective agents may be readily determined based the assays provided in Example 56.
  • agents that can be used: (A) anthracyclines (e.g., doxorubicin and mitoxantrone), (B) fluoropyrimidines (e.g., 5-FU), (C) folic acid antagonists (e.g., methotrexate), (D) podophylotoxins (e.g., etoposide), (E) camptothecins, (F) hydroxyureas, and (G) platinum complexes (e.g., cisplatin).
  • Anthracyclines e.g., doxorubicin and mitoxantrone
  • fluoropyrimidines e.g., 5-FU
  • C folic acid antagonists (e.g., methotrexate)
  • D podophylotoxins
  • E camptothecins
  • F hydroxyureas
  • platinum complexes e.g., cisplatin.
  • Anthracyclines have the
  • R groups are as follows: Ri is CH or CH 2 OH; R 2 is daunosamine or H; R 3 and R 4 are independently one of OH, NO2, NH , F, Cl, Br, I, CN, H or groups derived from these; R 5 is hydrogen, hydroxyl, or methoxy; and R 6- s are all hydrogen. Alternatively, R 5 and R 6 are hydrogen and R 7 and R 8 are alkyl or halogen, or vice versa. According to U.S. Patent 5,843,903, Ri may be a conjugated peptide. According to U.S. Patent 4,296,105, R 5 may be an ether linked alkyl group. According to U.S.
  • R 5 may be OH or an ether linked alkyl group. Ri may also be linked to the anthracycline ring by a group other than C(O), such as an alkyl or branched alkyl group having the C(O) linking moiety at its end, such as -CH 2 CH(CH 2 -X)C(0)-R ⁇ , wherein X is H or an alkyl group (see, e.g., U.S. Patent 4,215,062).
  • R 3 may have the following structure:
  • R-io may be H or form a secondary amine with a group such as an aromatic group, saturated or partially saturated 5 or 6 membered heterocyclic having at least one ring nitrogen (see U.S. Patent 5,843,903).
  • R-io may be derived from an amino acid, having the structure - C(0)CH(NHRn)(R 12 ), in which R-,-, is H, or forms a C 3-4 membered alkylene with R-I2.
  • R12 may be H, alkyl, aminoalkyl, amino, hydroxyl, mercapto, phenyl, benzyl or methylthio (see U.S. Patent 4,296,105).
  • exemplary anthracyclines are doxorubicin, daunorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, and carubicin. Suitable compounds have the structures:
  • Doxorubicin OCH 3 C(0)CH 2 OH OH out of ring plane
  • Epirubicin (4' epimer of OCH 3 C(0)CH 2 OH OH in ring plane doxorubicin)
  • Daunorubicin OCHs C(0)CH 3 OH out of ring plane
  • Idarubicin H C(0)CH 3 OH out of ring plane
  • Carubicin OH C(0)CH 3 OH out of ring plane
  • suitable anthracyclines are anthramycin, mitoxantrone, menogaril, nogalamycin, aclacinomycin A, olivomycin A, chromomycin A 3 , and plicamycin having the structures: R, R 2 R 3 Menogaril H OCH, H Nogalamycin O-sugar H COOCH 3 sugar Mitoxantrone
  • Other representative anthracyclines include, FCE 23762, a doxorubicin derivative (Quaglia et al., J. Liq. Chromatogr. 17(18):3911-3923, 1994), annamycin (Zou et al., J. Pharm. Sci. 82(11 ):1151-1154, 1993), ruboxyl (Rapoport et al., J. Controlled Release 58(2):153-162, 1999), anthracycline disaccharide doxorubicin analogue (Pratesi etal., Clin.
  • AD198 doxorubicin analogue (Traganos et al., Cancer Res. 5"/(14):3682-9, 1991), 4-demethoxy-3'-N-trifluoroacetyldoxorubicin (Horton et al., Drug Des. Delivery 6(2):123-9, 1990), 4'-epidoxorubicin (Drzewoski et al., Pol. J. Pharmacol. Pharm. 40(2):159-65, 1988; Weenen et al., Eur. J. Cancer Clin. Oncol. 20(7):919-26, 1984), alkylating cyanomorpholino doxorubicin derivative (Scudder ef al., J.
  • the therapeutic agent is a fluoropyrimidine analog, such as 5-fluorouracil, or an analogue or derivative thereof, including carmofur, doxifluridine, emitefur, tegafur, and floxuridine.
  • fluoropyrimidine analog such as 5-fluorouracil, or an analogue or derivative thereof, including carmofur, doxifluridine, emitefur, tegafur, and floxuridine.
  • Exemplary compounds have the structures:
  • fluoropyrimidine analogues include 5-FudR (5- fluoro-deoxyuridine), or an analogue or derivative thereof, including 5- iododeoxyuridine (5-ludR), 5-bromodeoxyuridine (5-BudR), fluorouridine triphosphate (5-FUTP), and fluorodeoxyuridine monophosphate (5-dFUMP).
  • 5-FudR 5- fluoro-deoxyuridine
  • an analogue or derivative thereof including 5- iododeoxyuridine (5-ludR), 5-bromodeoxyuridine (5-BudR), fluorouridine triphosphate (5-FUTP), and fluorodeoxyuridine monophosphate (5-dFUMP).
  • Exemplary compounds have the structures:
  • fluoropyrimidine analogues include N3-alkylated analogues of 5-fluorouracil (Kozai et al., J. Chem. Soc, Perkin Trans.
  • the therapeutic agent is a folic acid antagonist, such as methotrexate or derivatives or analogues thereof, including edatrexate, trimetrexate, raltitrexed, piritrexim, denopterin, tomudex, and pteropterin.
  • Methotrexate analogues have the following general structure:
  • R group may be selected from organic groups, particularly those groups set forth in U.S. Patent Nos. 5,166,149 and 5,382,582.
  • Ri may be N
  • R 2 may be N or C(CH 3 )
  • R 3 and R 3 ' may H or alkyl, e.g., CH 3
  • R 4 may be a single bond or NR, where R is H or alkyl group.
  • R 5 , 6 , 8 may be H, OCH 3 , or alternately they can be halogens or hydro groups.
  • R 7 is a side chain of the general structure:
  • the carboxyl groups in the side chain may be esterified or form a salt such as a Zn 2+ salt.
  • Rg and R10 can be NH 2 or may be alkyl substituted.
  • Exemplary folic acid antagonist compounds have the structures:
  • Pteridines Folic Acid Deriv., 1154-7, 1989 N-(L- ⁇ -aminoacyl) methotrexate derivatives (Cheung et al., Heterocycles 28(2):751-8, 1989), meta and ortho isomers of aminopterin (Rosowsky et al., J. Med. Chem. 32(12):2582, 1989), hydroxymethylmethotrexate (DE 267495), ⁇ -fluoromethotrexate (McGuire et al., Cancer Res. 49(16):4517-25, 1989), polyglutamyl methotrexate derivatives (Kumar et al., Cancer Res.
  • the therapeutic agent is a podophyllotoxin, or a derivative or an analogue thereof.
  • Exemplary compounds of this type are etoposide or teniposide, which have the following structures:
  • Other representative examples of podophyllotoxins include Cu(ll)- VP-16 (etoposide) complex (Tawa et al., Bioorg. Med. Chem. 6(7):1003-1008, 1998), pyrrolecarboxamidino-bearing etoposide analogues (Ji et al., Bioorg. Med. Chem. Lett.
  • camptothecins In another aspect, the therapeutic agent is camptothecin, or an analogue or derivative thereof. Camptothecins have the following general structure.
  • X is typically O, but can be other groups, e.g., NH in the case of 21-lactam derivatives.
  • R-i is typically H or OH, but may be other groups, e.g., a terminally hydroxylated C 1-3 alkane.
  • R 2 is typically H or an amino containing group such as (CH 3 ) 2 NHCH 2 , but may be other groups e.g., N0 2 , NH 2 , halogen (as disclosed in, e.g., U.S. Patent 5,552,156) or a short alkane containing these groups.
  • R 3 is typically H or a short alkyl such as C 2 H 5 .
  • R 4 is typically H but may be other groups, e.g., a methylenedioxy group with R-i.
  • camptothecin compounds include topotecan, irinotecan (CPT-11), 9-aminocamptothecin, 21-lactam-20(S)-camptothecin, 10,11-methylenedioxycamptothecin, SN-38, 9-nitrocamptothecin, 10- hydroxycamptothecin.
  • Exemplary compounds have the structures:
  • Camptothecins have the five rings shown here.
  • the ring labeled E must be intact (the lactone rather than carboxylate form) for maximum activity and minimum toxicity. Camptothecins are believed to function as topoisomerase I inhibitors and/or DNA cleavage agents.
  • f) Hydroxyureas The therapeutic agent of the present invention may be a hydroxyurea. Hydroxyureas have the following general structure:
  • Suitable hydroxyureas are disclosed in, for example, U.S. Patent No. 6,080,874, wherein Ri is:
  • R 2 is an alkyl group having 1-4 carbons and R 3 is one of H, acyl, methyl, ethyl, and mixtures thereof, such as a methylether.
  • R-i is a cycloalkenyl group, for example N-[3-[5-(4- fluorophenylthio)-furyl]-2-cyclopenten-1-yl]N-hydroxyurea
  • R2 is H or an alkyl group having 1 to 4 carbons and R 3 is H
  • X is H or a cation.
  • Other suitable hydroxyureas are disclosed in, e.g., U.S.
  • Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent No. 5,066,658, wherein R 2 and R 3 together with the adjacent nitrogen form:
  • hydroxyurea has the structure:
  • platinum complexes In another aspect, the therapeutic agent is a platinum compound.
  • suitable platinum complexes may be of Pt(ll) or Pt(IV) and have this basic structure:
  • X and Y are anionic leaving groups such as sulfate, phosphate, carboxylate, and halogen; R ⁇ ⁇ and R 2 are alkyl, amine, amino alkyl any may be further substituted, and are basically inert or bridging groups.
  • Pt(ll) complexes Zi and Z 2 are non-existent.
  • Pt(IV) Z-i and Z may be anionic groups such as halogen, hydroxy, carboxylate, ester, sulfate or phosphate. See, e.g., U.S. Patent Nos. 4,588,831 and 4,250,189.
  • Suitable platinum complexes may contain multiple Pt atoms. See, e.g., U.S. Patent Nos. 5,409,915 and 5,380,897.
  • platinum compounds are cisplatin, carboplatin, oxaliplatin, and miboplatin having the structures:
  • platinum compounds include (CPA) 2 Pt[DOLYM] and (DACH)Pt[DOLYM] cisplatin (Choi et al., Arch. Pharmacal Res. 22(2):151-156, 1999), Cis-[PtCI 2 (4,7-H-5-methyl-7- oxo]1 ,2,4[triazolo[1 ,5-a]pyrimidine) 2 ] (Navarro et al., J. Med. Chem. 41(3):332- 338, 1998), [Pt(cis-1 ,4-DACH)(trans-CI 2 )(CBDCA)] • 1 / 2 MeOH cisplatin (Shamsuddin et al., Inorg. Chem.
  • the total dose of doxorubicin applied to the implant should not exceed 25 mg (range of 0.1 ⁇ g to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 ⁇ g to 5 mg.
  • the dose per unit area i.e., the amount of drug as a function of the surface area of the portion of the implant to which drug is applied and/or incorporated
  • doxorubicin should be applied to the implant surface at a dose of 0.1 ⁇ g/mm 2 - 10 ⁇ g/mm 2 .
  • the above dosing parameters should be utilized in combination with the release rate of the drug from the implant surface such that a minimum concentration of 10 ⁇ 8 - 10 "4 M of doxorubicin is maintained on the surface. It is necessary to insure that surface drug concentrations exceed concentrations of doxorubicin known to be lethal to multiple species of bacteria and fungi (i.e., are in excess of 10 "4 M; although for some embodiments lower concentrations are sufficient).
  • doxorubicin is released from the surface of the implant such that anti-infective activity is maintained for a period ranging from several hours to several months.
  • the drug is released in effective concentrations for a period ranging from 1 week - 6 months.
  • analogues and derivatives of doxorubicin (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g., a compound twice as potent as doxorubicin is administered at half the above parameters, a compound half as potent as doxorubicin is administered at twice the above parameters, etc.).
  • the total dose of mitoxantrone applied should not exceed 5 mg (range of 0.01 ⁇ g to 5 mg).
  • the total amount of drug applied should be in the range of 0.1 ⁇ g to 3 mg.
  • the dose per unit area i.e., the amount of drug as a function of the surface area of the portion of the implant to which drug is applied and/or incorporated
  • mitoxantrone should be applied to the implant surface at a dose of 0.05 ⁇ g/mm 2 - 5 ⁇ g/mm 2 .
  • the above dosing parameters should be utilized in combination with the release rate of the drug from the implant surface such that a minimum concentration of 10 "4 - 10 "8 M of mitoxantrone is maintained. It is necessary to insure that drug concentrations on the implant surface exceed concentrations of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e., are in excess of 10 "5 M; although for some embodiments lower drug levels will be sufficient).
  • mitoxantrone is released from the surface of the implant such that anti-infective activity is maintained for a period ranging from several hours to several months.
  • the drug is released in effective concentrations for a period ranging from 1 week - 6 months.
  • analogues and derivatives of mitoxantrone (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g., a compound twice as potent as mitoxantrone is administered at half the above parameters, a compound half as potent as mitoxantrone is administered at twice the above parameters, etc.).
  • the total dose of 5-fluorouracil applied should not exceed 250 mg (range of 1.0 ⁇ g to 250 mg). ln a particularly preferred embodiment, the total amount of drug applied should be in the range of 10 ⁇ g to 25 mg.
  • the dose per unit area i.e., the amount of drug as a function of the surface area of the portion of the implant to which drug is applied and/or incorporated
  • 5-fluorouracil should be applied to the implant surface at a dose of 0.5 ⁇ g/mm 2 - 50 ⁇ g/mm 2 .
  • the above dosing parameters should be utilized in combination with the release rate of the drug from the implant surface such that a minimum concentration of 10 "4 - 10 "7 M of 5-fluorouracil is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of 5-fluorouracil known to be lethal to numerous species of bacteria and fungi (i.e., are in excess of 10 "4 M; although for some embodiments lower drug levels will be sufficient).
  • 5-fluorouracil is released from the implant surface such that anti- infective activity is maintained for a period ranging from several hours to several months.
  • the drug is released in effective concentrations for a period ranging from 1 week - 6 months.
  • analogues and derivatives of 5-fluorouracil (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g., a compound twice as potent as 5-fluorouracil is administered at half the above parameters, a compound half as potent as 5-fluorouracil is administered at twice the above parameters, etc.).
  • the total dose of etoposide applied should not exceed 25 mg (range of 0.1 ⁇ g to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 ⁇ g to 5 mg.
  • the dose per unit area i.e., the amount of drug as a function of the surface area of the portion of the implant to which drug is applied and/or incorporated should fall within the range of 0.01 ⁇ g - 100 ⁇ g per mm 2 of surface area.
  • etoposide should be applied to the implant surface at a dose of 0.1 ⁇ g/mm 2 - 10 ⁇ g/mm 2 .
  • the above dosing parameters should be utilized in combination with the release rate of the drug from the implant surface such that a concentration of 10 "4 - 10 "7 M of etoposide is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of etoposide known to be lethal to a variety of bacteria and fungi (i.e., are in excess of 10 "5 M; although for some embodiments lower drug levels will be sufficient).
  • etoposide is released from the surface of the implant such that anti-infective activity is maintained for a period ranging from several hours to several months.
  • the drug is released in effective concentrations for a period ranging from 1 week - 6 months.
  • analogues and derivatives of etoposide (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g., a compound twice as potent as etoposide is administered at half the above parameters, a compound half as potent as etoposide is administered at twice the above parameters, etc.).
  • anthracyclines e.g., doxorubicin or mitoxantrone
  • fluoropyrimidines e.g., 5-fluorouracil
  • folic acid antagonists e.g., methotrexate and/or podophylotoxins (e.g., etoposide)
  • podophylotoxins e.g., etoposide
  • an anti-infective agent e.g., anthracyclines (e.g., doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists (e.g., methotrexate and/or podophylotoxins (e.g., etoposide)
  • anthracyclines e.g., doxorubicin or mitoxantrone
  • fluoropyrimidines e.g., 5-fluorouracil
  • folic acid antagonists e.g., methotrexate and/or podophylotoxins (e.g., etoposide)
  • traditional antibiotic and/or antifungal agents e.g., doxorubicin or mitoxantrone
  • fluoropyrimidines e.g., 5-fluorouracil
  • folic acid antagonists e.g., methotrex
  • the anti-infective agent may be further combined with anti-thrombotic and/or antiplatelet agents (for example, heparin, dextran sulphate, danaparoid, lepirudin, hirudin, AMP, adenosine, 2-chloroadenosine, aspirin, phenylbutazone, indomethacin, meclofenamate, hydrochloroquine, dipyridamole, iloprost, ticlopidine, clopidogrel, abcixamab, eptifibatide, tirofiban, streptokinase, and/or tissue plasminogen activator) to enhance efficacy.
  • anti-thrombotic and/or antiplatelet agents for example, heparin, dextran sulphate, danaparoid, lepirudin, hirudin, AMP, adenosine, 2-chloroadenosine, aspirin, phenylbutazone
  • one or more other pharmaceutically active agents can be incorporated into the present compositions and devices to improve or enhance efficacy.
  • additional therapeutically active agents include, by way of example and not limitation, anti-thrombotic agents, anti-proliferative agents, anti-inflammatory agents, neoplastic agents, enzymes, receptor antagonists or agonists, hormones, antibiotics, antimicrobial agents, antibodies, cytokine inhibitors, IMPDH (inosine monophosplate dehydrogenase) inhibitors tyrosine kinase inhibitors, MMP inhibitors, p38 MAP kinase inhibitors, immunosuppressants, apoptosis antagonists, caspase inhibitors, and JNK inhibitors.
  • anti-thrombotic agents include, by way of example and not limitation, anti-thrombotic agents, anti-proliferative agents, anti- inflammatory agents, neoplastic agents, enzymes, receptor antagonists or agonists, hormones, antibiotics, antimicrobial agents, antibodies, cytokine inhibitors, IMPDH (inosine monophosplate dehydrogenase) inhibitors tyrosine
  • Implantable electrical devices and compositions for use with implantable electrical devices may further include an anti-thrombotic agent and/or antiplatelet agent and/or a thrombolytic agent, which reduces the likelihood of thrombotic events upon implantation of a medical implant.
  • a device is coated on one aspect with a composition which inhibits fibrosis (and/or restenosis), as well as being coated with a composition or compound which prevents thrombosis on another aspect of the device.
  • anti-thrombotic and/or antiplatelet and/or thrombolytic agents include heparin, heparin fragments, organic salts of heparin, heparin complexes (e.g., benzalkonium heparinate, tridodecylammonium heparinate), dextran, sulfonated carbohydrates such as dextran sulphate, coumadin, coumarin, heparinoid, danaparoid, argatroban chitosan sulfate, chondroitin sulfate, danaparoid, lepirudin, hirudin, AMP, adenosine, 2-chloroadenosine, acetylsalicylic acid, phenylbutazone, indomethacin, meclofenamate, hydrochloroquine, dipyridamole, iloprost, streptokinase, factor Xa inhibitors, such as D
  • Further examples include plasminogen, lys- plasminogen, alpha-2-antiplasmin, urokinase, aminocaproic acid, ticlopidine, clopidogrel, trapidil (triazolopyrimidine), naftidrofuryl, auriritricarboxylic acid and glycoprotein llb/llla inhibitors such as abcixamab, eptifibatide, and tirogiban.
  • compositions for use with electrical devices may be or include a hydrophilic polymer gel that itself has anti-thrombogenic properties.
  • the composition can be in the form of a coating that can comprise a hydrophilic, biodegradable polymer that is physically removed from the surface of the device over time, thus reducing adhesion of platelets to the device surface.
  • the gel composition can include a polymer or a blend of polymers.
  • Representative examples include alginates, chitosan and chitosan sulfate, hyaluronic acid, dextran sulfate, PLURONIC polymers (e.g., F-127 or F87), chain extended PLURONIC polymers, various polyester-polyether block copolymers of various configurations (e.g., AB, ABA, or BAB, where A is a polyester such as PLA, PGA, PLGA, PCL or the like), examples of which include MePEG-PLA, PLA-PEG-PLA, and the like).
  • PLURONIC polymers e.g., F-127 or F87
  • chain extended PLURONIC polymers e.g., various polyester-polyether block copolymers of various configurations (e.g., AB, ABA, or BAB, where A is a polyester such as PLA, PGA, PLGA, PCL or the like), examples of which include MePEG-PLA, PLA-PEG-PL
  • the anti-thrombotic composition can include a crosslinked gel formed from a combination of molecules (e.g., PEG) having two or more terminal electrophilic groups and two or more nucleophilic groups.
  • Electrical devices and compositions for use with implantable electrical devices may further include a compound which acts to have an inhibitory effect on pathological processes in or around the treatment site.
  • the agent may be selected from one of the following classes of compounds: anti-inflammatory agents (e.g., dexamethasone, cortisone, fludrocortisone, prednisone, prednisolone, 6 ⁇ -methylprednisolone, triamcinolone, betamethasone, and aspirin); MMP inhibitors (e.g., batimistat, marimistat, TIMP's representative examples of which are included in U.S. Patent Nos.
  • anti-inflammatory agents e.g., dexamethasone, cortisone, fludrocortisone, prednisone, prednisolone, 6 ⁇ -methylprednisolone, triamcinolone, betamethasone, and aspirin
  • MMP inhibitors e.g., batimistat, marimistat, TIMP's representative examples of which are included in U.S. Patent Nos.
  • WO 00/63204A2 WO 01/21591 A1 , WO 01/35959A1 , WO 01/74811A2, WO 02/18379A2, WO 02/064594A2, WO 02/083622A2, WO 02/094842A2,WO 02/096426A1 , WO 02/101015A2, WO 02/103000A2, WO 03/008413A1 , WO 03/016248A2, WO 03/020715A1 , WO 03/024899A2, WO 03/031431 A1 , WO 03/040103A1 , WO 03/053940A1 , WO 03/053941 A2, WO 03/063799A2, WO 03/079986A2, WO 03/080024A2, WO 03/082287A1 , WO 97/44467A1 , WO 99/01449A1 , and WO 99/58523A1), and immunomodulatory agents
  • Patent No. 6,258,823 and everolimus and derivatives thereof (e.g., U.S. Patent No. 5,665,772).
  • Further representative examples of sirolimus analogues and derivatives include ABT-578 and those found in PCT Publication Nos.
  • biologically active agents which may be combined with implantable electrical devices according to the invention include tyrosine kinase inhibitors, such as imantinib, ZK-222584, CGP-52411 , CGP- 53716, NVP-AAK980-NX, CP-127374, CP-564959, PD-171026, PD-173956, PD-180970, SU-0879, and SKI-606; MMP inhibitors such as nimesulide, PKF- 241-466, PKF-242-484, CGS-27023A, SAR-943, primomastat, SC-77964, PNU-171829, AG-3433, PNU-142769, SU-5402, and dexlipotam; p38 MAP kinase inhibitors such as include CGH-2466 and PD-98-59; immunosuppressants such as argyrin B, macrocyclic lactone, ADZ-62-826, CCI-779, t
  • the electrical device may further include an antibiotic (e.g., amoxicillin, trimethoprim-sulfamethoxazole, azithromycin, clarithromycin, amoxicillin-clavulanate, cefprozil, cefuroxime, cefpodoxime, or cefdinir).
  • an antibiotic e.g., amoxicillin, trimethoprim-sulfamethoxazole, azithromycin, clarithromycin, amoxicillin-clavulanate, cefprozil, cefuroxime, cefpodoxime, or cefdinir.
  • a polymeric composition comprising a fibrosis- inhibiting agent is combined with an agent that can modify metabolism of the agent in vivo to enhance efficacy of the fibrosis-inhibiting agent.
  • One class of therapeutic agents that can be used to alter drug metabolism includes agents capable of inhibiting oxidation of the anti-scarring agent by cytochrome P450 (CYP).
  • compositions include a fibrosis- inhibiting agent (e.g., paclitaxel, rapamycin, everolimus) and a CYP inhibitor, which may be combined (e.g., coated) with any of the devices described herein.
  • a fibrosis- inhibiting agent e.g., paclitaxel, rapamycin, everolimus
  • a CYP inhibitor e.g., flavones, azole antifungals, macrolide antibiotics, HIV protease inhibitors, and anti-sense oligomers.
  • Devices comprising a combination of a fibrosis-inhibiting agent and a CYP inhibitor may be used to treat a variety of proliferative conditions that can lead to undesired scarring of tissue, including intimal hyperplasia, surgical adhesions, and tumor growth.
  • a device incorporates or is coated on one aspect, portion or surface with a composition which inhibits fibrosis (and/or restenosis), as well as with a composition or compound which promotes fibrosis on another aspect, portion or surface of the device.
  • agents that promote fibrosis include silk and other irritants (e.g., talc, wool (including animal wool, wood wool, and synthetic wool), talcum powder, copper, metallic beryllium (or its oxides), quartz dust, silica, crystalline silicates), polymers (e.g., polylysine, polyurethanes, poly( ethylene terephthalate), PTFE, poly(alkylcyanoacrylates), and poly(ethylene-co-vinylacetate); vinyl chloride and polymers of vinyl chloride; peptides with high lysine content; growth factors and inflammatory cytokines involved in angiogenesis, fibroblast migration, fibroblast proliferation, ECM synthesis and tissue remodeling, such as epidermal growth factor (EGF) family, transforming growth factor- ⁇ (TGF- ⁇ ), transforming growth factor- ⁇ (TGF- ⁇ -1 , TGF- ⁇ -2, TGF- ⁇ -3, platelet-derived growth factor (PDGF), fibroblast growth factor (acidic -
  • CTGF connective tissue growth factor
  • inflammatory microcrystals e.g., crystalline minerals such as crystalline silicates
  • bromocriptine methylsergide, methotrexate, chitosan, N-carboxybutyl chitosan, carbon tetrachloride, thioacetamide, fibrosin, ethanol, bleomycin, naturally occurring or synthetic peptides containing the Arg-Gly-Asp (RGD) sequence, generally at one or both termini (see, e.g., U.S. Patent No. 5,997,895), and tissue adhesives, such as cyanoacrylate and crosslinked poly(ethylene glycol) - methylated collagen compositions.
  • tissue adhesives such as cyanoacrylate and crosslinked poly(ethylene glycol) - methylated collagen compositions.
  • fibrosis-inducing agents include bone morphogenic proteins (e.g., BMP-2, BMP- 3, BMP-4, BMP-5, BMP-6 (Vgr-1 ), BMP-7 (OP-1 ), BMP-8, BMP-9, BMP-10, BMP-11 , BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16.
  • BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7 are of particular utility.
  • Bone morphogenic proteins are described, for example, in U.S. Patent Nos.
  • fibrosis-inducing agents include components of extracellular matrix (e.g., fibronectin, fibrin, fibrinogen, collagen (e.g., bovine collagen), including fibrillar and non-fibrillar collagen, adhesive glycoproteins, proteoglycans (e.g., heparin sulfate, chondroitin sulfate, dermatan sulfate), hyaluronan, secreted protein acidic and rich in cysteine (SPARC), thrombospondins, tenacin, and cell adhesion molecules (including integrins, vitronectin, fibronectin, laminin, hyaluronic acid, elastin, bitronectin), proteins found in basement membranes, and fibrosin) and inhibitors of matrix metalloproteinases, such as TIMPs (tissue inhibitors of matrix metalloproteinases) and synthetic TIMPs, such as, e.g., marimistat,
  • paclitaxel may be understood to refer to not only the common chemically available form of paclitaxel, but analogues (e.g., TAXOTERE, as noted above) and paclitaxel conjugates (e.g., paclitaxel-PEG, paclitaxel-dextran, or paclitaxel-xylos).
  • analogues e.g., TAXOTERE, as noted above
  • paclitaxel conjugates e.g., paclitaxel-PEG, paclitaxel-dextran, or paclitaxel-xylos.
  • agents set forth above may be noted within the context of one class, many of the agents listed in fact have multiple biological activities. Further, more than one therapeutic agent may be utilized at a time (i.e., in combination), or delivered sequentially.
  • Drug dose can be calculated as a function of dose (i.e., amount) per unit area of the portion of the device being coated. Surface area can be measured or determined by methods known to one of ordinary skill in the art. Total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Drugs are to be used at concentrations that range from several times more than to 10%, 5%, or even less than 1% of the concentration typically used in a single chemotherapeutic systemic dose application.
  • the drug is released in effective concentrations for a period ranging from 1 - 90 days.
  • the fibrosis-inhibiting agents used alone or in combination, should be administered under the following dosing guidelines:
  • electrical devices may be used in combination with a composition that includes an anti-scarring agent.
  • the total amount (dose) of anti-scarring agent in or on the device may be in the range of about 0.01 ⁇ g-10 ⁇ g, or 10 ⁇ g-10 mg, or 10 mg-250 mg, or 250 mg-1000 mg, or 1000 mg-2500 mg.
  • the dose (amount) of anti-scarring agent per unit area of device surface to which the agent is applied may be in the range of about 0.01 ⁇ g/mm 2 - 1 ⁇ g/mm 2 , or 1 ⁇ g/mm 2 - 10 ⁇ g/mm 2 , or 10 ⁇ g/mm 2 - 250 ⁇ g/mm 2 , 250 ⁇ g/mm 2 - 1000 ⁇ g/mm 2 , or 1000 ⁇ g/mm 2 - 2500 ⁇ g/mm 2 . It should be apparent to one of skill in the art that potentially any anti-scarring agent described above may be utilized alone, or in combination, in the practice of this embodiment.
  • the present invention provides a medical device contain an angiogenesis inhibitor in a dosage as set forth above.
  • the present invention provides a medical device containing a 5-lipoxygenase inhibitor or antagonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a chemokine receptor antagonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a cell cycle inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an anthracycline (e.g., doxorubicin and mitoxantrone) in a dosage as set forth above.
  • an anthracycline e.g., doxorubicin and mitoxantrone
  • the present invention provides a medical device containing a taxane (e.g., paclitaxel or an analogue or derivative of paclitaxel) in a dosage as set forth above.
  • the present invention provides a medical device containing a vinca alkaloid in a dosage as set forth above.
  • the present invention provides a medical device containing a camptothecin or an analogue or derivative thereof in a dosage as set forth above.
  • the present invention provides a medical device containing a platinum compound in a dosage as set forth above.
  • the present invention provides a medical device containing a nitrosourea in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a nitroimidazole in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a folic acid antagonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a cytidine analogue in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a pyrimidine analogue in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a fluoropyrimidine analogue in a dosage as set forth above.
  • the present invention provides a medical device containing a purine analogue in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a nitrogen mustard in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a hydroxyurea in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a mytomicin in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an alkyl sulfonate in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a benzamide in a dosage as set forth above.
  • the present invention provides a medical device containing a nicotinamide in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a halogenated sugar in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a DNA alkylating agent in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an anti-microtubule agent in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a topoisomerase inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a DNA cleaving agent in a dosage as set forth above.
  • the present invention provides a medical device containing an antimetabolite in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an agent that inhibits adenosine deaminase in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an agent that inhibits purine ring synthesis in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a nucleotide interconversion inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an agent that inhibits dihydrofolate reduction in a dosage as set forth above.
  • the present invention provides a medical device containing an agent that blocks thymidine monophosphate function in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an agent that causes DNA damage in a dosage as set forth above, ln various aspects, the present invention provides a medical device containing a DNA intercalation agent in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an agent that is a RNA synthesis inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an agent that is a pyrimidine synthesis inhibitor in a dosage as set forth above.
  • the present invention provides a medical device containing an agent that inhibits ribonucleotide synthesis in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an agent that inhibits thymidine monophosphate synthesis in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an agent that inhibits DNA synthesis in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an agent that causes DNA adduct formation in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an agent that inhibits protein synthesis in a dosage as set forth above.
  • the present invention provides a medical device containing an agent that inhibits microtubule function in a dosage as set forth above.
  • the present invention provides a medical device containing an immunomodulatory agent (e.g., sirolimus, everolimus, tacrolimus, or an analogue or derivative thereof) in a dosage as set forth above.
  • the present invention provides a medical device containing a heat shock protein 90 antagonist (e.g., geldanamycin) in a dosage as set forth above.
  • the present invention provides a medical device containing an HMGCoA reductase inhibitor (e.g., simvastatin) in a dosage as set forth above.
  • the present invention provides a medical device containing an inosine monophosphate dehydrogenase inhibitor (e.g., mycophenolic acid, 1-alpha-25 dihydroxy vitamin D 3 ) in a dosage as set forth above.
  • an inosine monophosphate dehydrogenase inhibitor e.g., mycophenolic acid, 1-alpha-25 dihydroxy vitamin D 3
  • the present invention provides a medical device containing an NF kappa B inhibitor (e.g., Bay 11-7082) in a dosage as set forth above.
  • the present invention provides a medical device containing an antimycotic agent (e.g., sulconizole) in a dosage as set forth above.
  • the present invention provides a medical device containing a p38 MAP Kinase inhibitor (e.g., SB202190) in a dosage as set forth above.
  • the present invention provides a medical device containing a cyclin dependent protein kinase inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an epidermal growth factor kinase inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an elastase inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a factor Xa inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a farnesyltransferase inhibitor in a dosage as set forth above.
  • the present invention provides a medical device containing a fibrinogen antagonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a guanylate cyclase stimulant in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a hydroorotate dehydrogenase inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an IKK2 inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an IL-1 antagonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an ICE antagonist in a dosage as set forth above.
  • the present invention provides a medical device containing an IRAK antagonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an IL-4 agonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a leukotriene inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an MCP-1 antagonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a MMP inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an NO antagonist in a dosage as set forth above.
  • the present invention provides a medical device containing a phosphodiesterase inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a TGF beta inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a thromboxane A2 antagonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a TNF ⁇ antagonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a TACE inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a tyrosine kinase inhibitor in a dosage as set forth above.
  • the present invention provides a medical device containing a vitronectin inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a fibroblast growth factor inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a protein kinase inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a PDGF receptor kinase inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an endothelial growth factor receptor kinase inhibitor in a dosage as set forth above.
  • the present invention provides a medical device containing a retinoic acid receptor antagonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a platelet derived growth factor receptor kinase inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a fibrinogen antagonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a bisphosphonate in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a phospholipase A1 inhibitor in a dosage as set forth above.
  • the present invention provides a medical device containing a histamine H1/H2/H3 receptor antagonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a macrolide antibiotic in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a GPIIb Ilia receptor antagonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an endothelin receptor antagonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a peroxisome proliferator-activated receptor agonist in a dosage as set forth above.
  • the present invention provides a medical device containing an estrogen receptor agent in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a somastostatin analogue in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a neurokinin 1 antagonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a neurokinin 3 antagonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a VLA-4 antagonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an osteoclast inhibitor in a dosage as set forth above.
  • the present invention provides a medical device containing a DNA topoisomerase ATP hydrolyzing inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an angiotensin I converting enzyme inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an angiotensin II antagonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an enkephalinase inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer in a dosage as set forth above.
  • the present invention provides a medical device containing a protein kinase C inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a ROCK (rho-associated kinase) inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a CXCR3 inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a Itk inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a cytosolic phospholipase A 2 -alpha inhibitor in a dosage as set forth above.
  • the present invention provides a medical device containing a PPAR agonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an Immunosuppressant in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an Erb inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an apoptosis agonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a lipocortin agonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a VCAM-1 antagonist in a dosage as set forth above.
  • the present invention provides a medical device containing a collagen antagonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing an alpha 2 integrin antagonist in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a TNF alpha inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a nitric oxide inhibitor in a dosage as set forth above. In various aspects, the present invention provides a medical device containing a cathepsin inhibitor in a dosage as set forth above. Provided below are exemplary dosage ranges for a variety of anti- scarring agents which can be used in conjunction with electrical devices in accordance with the invention.
  • A) Cell cycle inhibitors including doxorubicin and mitoxantrone including doxorubicin and mitoxantrone.
  • Doxorubicin analogues and derivatives thereof total dose not to exceed 25 mg (range of 0.1 ⁇ g to 25 mg); preferred 1 ⁇ g to 5 mg.
  • Minimum concentration of 10 "8 - 10 "4 M of doxorubicin is to be maintained on the device surface.
  • Mitoxantrone and analogues and derivatives thereof total dose not to exceed 5 mg (range of 0.01 ⁇ g to 5 mg); preferred 0.1 ⁇ g to 3 mg.
  • the dose per unit area of the device of 0.01 ⁇ g - 20 ⁇ g per mm 2 ; preferred dose of 0.05 ⁇ g/mm 2 - 5 ⁇ g/mm 2 .
  • Minimum concentration of 10 "8 - 10 "4 M of mitoxantrone is to be maintained on the device surface.
  • the dose per unit area of the device of 0.1 ⁇ g - 10 ⁇ g per mm 2 ; preferred dose of 0.25 ⁇ g/mm 2 - 5 ⁇ g/mm 2 .
  • C Cell cycle inhibitors such as podophyllotoxins (e.g., etoposide): total dose not to exceed 25 mg (range of 0.1 ⁇ g to 25 mg); preferred 1 ⁇ g to 5 mg. The dose per unit area of the device of 0.01 ⁇ g - 100 ⁇ g per mm 2 ; preferred dose of 0.1 ⁇ g/mm 2 - 10 ⁇ g/mm 2 . Minimum concentration of 10 "8 - 10 "4 M of etoposide is to be maintained on the device surface.
  • D Immunomodulators including sirolimus and everolimus.
  • Sirolimus i.e., Rapamycin, RAPAMUNE: Total dose not to exceed 10 mg (range of 0.1 ⁇ g to 10 mg); preferred 10 ⁇ g to 1 mg.
  • Minimum concentration of 10 "8 - 10 "4 M is to be maintained on the device surface.
  • Everolimus and derivatives and analogues thereof Total dose should not exceed 10 mg (range of 0.1 ⁇ g to 10 mg); preferred 10 ⁇ g to 1 mg.
  • Minimum concentration of 10 "8 - 10 "4 M of everolimus is to be maintained on the device surface.
  • Heat shock protein 90 antagonists e.g., geldanamycin
  • analogues and derivatives thereof total dose not to exceed 20 mg (range of 0.1 ⁇ g to 20 mg); preferred 1 ⁇ g to 5 mg.
  • HMGCoA reductase inhibitors e.g., simvastatin
  • analogues and derivatives thereof total dose not to exceed 2000 mg (range of 10.0 ⁇ g to 2000 mg); preferred 10 ⁇ g to 300 mg.
  • the dose per unit area of the device of 1.0 ⁇ g - 1000 ⁇ g per mm 2 ; preferred dose of 2.5 ⁇ g/mm 2 - 500 ⁇ g/mm 2 .
  • Minimum concentration of 10 "8 - 10 "3 M of simvastatin is to be maintained on the device surface.
  • Inosine monophosphate dehydrogenase inhibitors e.g., mycophenolic acid, 1-alpha-25 dihydroxy vitamin D 3
  • analogues and derivatives thereof total dose not to exceed 2000 mg (range of 10.0 ⁇ g to 2000 mg); preferred 10 ⁇ g to 300 mg.
  • the dose per unit area of the device of 1.0 ⁇ g - 1000 ⁇ g per mm 2 ; preferred dose of 2.5 ⁇ g/mm 2 - 500 ⁇ g/mm 2 .
  • Minimum concentration of 10 "8 - 10 "3 M of mycophenolic acid is to be maintained on the device surface.
  • (H) NF kappa B inhibitors e.g., Bay 11-7082 and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 1.0 ⁇ g to 200 mg); preferred 1 ⁇ g to 50 mg.
  • the dose per unit area of the device of 1.0 ⁇ g - 100 ⁇ g per mm 2 ; preferred dose of 2.5 ⁇ g/mm 2 - 50 ⁇ g/mm 2 .
  • Minimum concentration of 10 "8 - 10 "4 M of Bay 11- 7082 is to be maintained on the device surface.
  • Antimycotic agents e.g., sulconizole
  • analogues and derivatives thereof total dose not to exceed 2000 mg (range of 10.0 ⁇ g to 2000 mg); preferred 10 ⁇ g to 300 mg.
  • the dose per unit area of the device of 1.0 ⁇ g - 000 ⁇ g per mm ,2;. preferred dose of 2.5 ⁇ g/mm 2 - 500 ⁇ g/mm 2 .
  • Minimum concentration of 10 "8 - 10 "3 M of sulconizole is to be maintained on the device surface.
  • p38 MAP kinase inhibitors e.g., SB202190
  • analogues and derivatives thereof total dose not to exceed 2000 mg (range of 10.0 ⁇ g to 2000 mg); preferred 10 ⁇ g to 300 mg.
  • the dose per unit area of the device of 1.0 ⁇ g - 1000 ⁇ g per mm 2 ; preferred dose of 2.5 ⁇ g/mm 2 - 500 ⁇ g/mm 2 .
  • Minimum concentration of 10 "8 - 10 "3 M of SB202190 is to be maintained on the device surface.
  • Anti-angiogenic agents e.g., halofuginone bromide and analogues and derivatives thereof: total dose not to exceed 10 mg (range of 0.1 ⁇ g to 10 mg); preferred 1 ⁇ g to 3 mg.
  • the dose per unit area of the device of 0.1 ⁇ g - 10 ⁇ g per mm 2 ; preferred dose of 0.20 ⁇ g/mm 2 - 5 ⁇ g/mm 2 .
  • Minimum concentration of 10 "8 - 10 "4 M of halofuginone bromide is to be maintained on the device surface.
  • immunomodulators and appropriate dosage ranges for use with neurostimulation and CRM devices include the following: (A) Biolimus and derivatives and analogues thereof: Total dose should not exceed 10 mg (range of 0.1 ⁇ g to 10 mg); preferred 10 ⁇ g to 1 mg. The dose per unit area of 0.1 ⁇ g - 100 ⁇ g per mm 2 of surface area; preferred dose of 0.3 ⁇ g/mm 2 - 10 ⁇ g/mm 2 . Minimum concentration of 10 "8 - 10 "4 M of everolimus is to be maintained on the device surface.
  • Tresperimus and derivatives and analogues thereof Total dose should not exceed 10 mg (range of 0.1 ⁇ g to 10 mg); preferred 10 ⁇ g to 1 mg.
  • Minimum concentration of 10 "8 - 10 "4 M of tresperimus is to be maintained on the device surface.
  • Auranofin and derivatives and analogues thereof Total dose should not exceed 10 mg (range of 0.1 ⁇ g to 10 mg); preferred 10 ⁇ g to 1 mg.
  • Minimum concentration of 10 "8 - 10 "4 M of auranofin is to be maintained on the device surface.
  • (F) Pimecrolimus and derivatives and analogues thereof Total dose should not exceed 10 mg (range of 0.1 ⁇ g to 10 mg); preferred 10 ⁇ g to 1 mg.
  • Minimum concentration of 10 "8 - 10 "4 M of pimecrolimus is to be maintained on the device surface and
  • Minimum concentration of 10 "8 - 10 "4 M of ABT-578 is to be maintained on the device surface.
  • anti-microtubule agents and appropriate dosage ranges for use with ear ventilation devices include vinca alkaloids such as vinblastine and vincristine sulfate and analogues and derivatives thereof: total dose not to exceed 10 mg (range of 0.1 ⁇ g to 10 mg); preferred 1 ⁇ g to 3 mg.
  • Dose per unit area of the device of 0.1 ⁇ g - 10 ⁇ g per mm 2 ; preferred dose of 0.25 ⁇ g/mm 2 - 5 ⁇ g/mm 2 . Minimum concentration of 10 " 8 - 10 "4 M of drug is to be maintained on the device surface.
  • D. Methods for Generating Medical Devices and Implants Which Release a Fibrosis-inhibiting (or Gliosis-inhibiting) Agent In the practice of this invention, drug-coated or drug-impregnated implants and medical devices are provided which inhibit fibrosis (or gliosis) in and around the device, lead and/or electrode of neurostimulation or cardiac rhythm management (CRM) devices.
  • CRM cardiac rhythm management
  • fibrosis is inhibited by local, regional or systemic release of specific pharmacological agents that become localized to the tissue adjacent to the device or implant.
  • fibrotic (or gliotic) reaction may adversely affect the functioning of the device or the biological problem for which the device was implanted or used.
  • fibrotic (or gliotic) encapsulation of the electrical lead or the growth of fibrous/glial tissue between the lead and the target nerve tissue slows, impairs, or interrupts electrical transmission of the impulse from the device to the tissue.
  • the present invention provides electrical devices that include an anti-scarring (or anti-gliotic) agent or a composition that includes an anti-scarring (or anti-gliotic) agent such that the overgrowth of granulation (or gliotic) tissue is inhibited or reduced.
  • Methods for incorporating fibrosis-inhibiting (or gliosis-inhibiting) compositions onto or into CRM or neurostimulator devices include: (a) directly affixing to the device, lead and/or the electrode a fibrosis-inhibiting (or gliosis- inhibiting) composition (e.g., by either a spraying process or dipping process as described above, with or without a carrier), (b) directly incorporating into the device, lead and/or the electrode a fibrosis-inhibiting (or gliosis-inhibiting) composition (e.g., by either a spraying process or dipping process as described above, with or without a carrier (c) by coating the device, lead and/or the electrode with a substance such as a hydrogel which may in turn absorb the fibrosis-inhibiting (or gliosis-inhibiting) composition, (d) by interweaving fibrosis- inhibiting (or gliosis-inhibiting) composition coated
  • the coating process can be performed in such a manner as to: (a) coat the non-electrode portions of the lead or device; (b) coat the electrode portion of the lead; (c) coat the sensor part of the lead; or (d) coat all or parts of the entire device with the fibrosis- inhibiting (or gliosis-inhibiting) composition.
  • the fibrosis-inhibiting (or gliosis-inhibiting) agent can be mixed with the materials that are used to make the device, lead and/or electrode such that the fibrosis- inhibiting agent is incorporated into the final product.
  • the fibrosis-inhibiting (or gliosis-inhibiting) agent can be applied directly or indirectly to the tissue adjacent to the CRM or neurostimulator device (preferably near the electrode-tissue interface).
  • the fibrosis-inhibiting (or gliosis inhibiting) agent with or without a polymeric, non-polymeric, or secondary carrier: (a) to the lead and/or electrode surface (e.g., as an injectable, paste, gel or mesh) during the implantation procedure); (b) to the surface of the tissue (e.g., as an injectable, paste, gel, in situ forming gel or mesh) prior to, immediately prior to, or during, implantation of the CRM or neurostimulation device, lead and/or electrode; (c) to the surface of the lead and/or electrode and/or the tissue surrounding the implanted lead and/or electrode (e.g., as an injectable, paste, gel, in situ forming gel or mesh) immediately after to the implantation of the CRM or neurostimulation device, lead and/or electrode; (d) by topical application of the anti-fibrosis (or gliosis) agent into the anatomical space where the CRM or neurostimulation device, lead and/or
  • Combination therapies i.e., combinations of therapeutic agents and combinations with antithrombotic and/or antiplatelet agents
  • 2) Systemic, Regional and Local Delivery of Fibrosis-inhibiting (or Gliosis-inhibiting) Agents A variety of drug-delivery technologies are available for systemic, regional and local delivery of therapeutic agents.
  • drug delivery catheters are advanced through the circulation or inserted directly into tissues under radiological guidance until they reach the desired anatomical location.
  • the fibrosis inhibiting agent can then be released from the catheter lumen in high local concentrations in order to deliver therapeutic doses of the drug to the tissue surrounding the device or implant; (b) drug localization techniques such as magnetic, ultrasonic or MRI-guided drug delivery; (c) chemical modification of the fibrosis-inhibiting (or gliosis-inhibiting) drug or formulation designed to increase uptake of the agent into damaged tissues (e.g., antibodies directed against damaged or healing tissue components such as macrophages, neutrophils, smooth muscle cells, fibroblasts, extracellular matrix components, neovascular tissue); (d) chemical modification of the fibrosis-inhibiting (or gliosis-inhibiting) drug or formulation designed to localize the drug to areas of bleeding or disrupted vasculature; and/or (e) direct injection of the fibrosis- inhibiting (or gliosis-inhibiting) agent, for example, under endoscopic vision.
  • drug localization techniques such as magnetic, ultrasonic or
  • the tissue surrounding the CRM or neurostimulation device can be treated with a fibrosis-inhibiting (or gliosis-inhibiting) agent prior to, during, or after the implantation procedure.
  • a fibrosis-inhibiting (or gliosis- inhibiting) agent or a composition comprising a fibrosis-inhibiting (or gliosis- inhibiting) agent may be infiltrated around the device or implant by applying the composition directly and/or indirectly into and/or onto (a) tissue adjacent to the medical device; (b) the vicinity of the medical device-tissue interface; (c) the region around the medical device; and (d) tissue surrounding the medical device.
  • certain polymeric carriers themselves can help prevent the formation of fibrous or gliotic tissue around the CRM or neuroimplant. These carriers are particularly useful for the practice of this embodiment, either alone, or in combination with a fibrosis (or gliosis) inhibiting composition.
  • the following polymeric carriers can be infiltrated (as described in the previous paragraph) into the vicinity of the electrode-tissue interface and include: (a) sprayable collagen-containing formulations such as COSTASIS and CT3, either alone, or loaded with a fibrosis-inhibiting (or gliosis-inhibiting) agent, applied to the implantation site (or the implant/device surface); (b) sprayable PEG-containing formulations such as COSEAL, FOCALSEAL, SPRAYGEL or DURASEAL, either alone, or loaded with a fibrosis-inhibiting (or gliosis- inhibiting) agent, applied to the implantation site (or the implant/device surface); (c) fibrinogen-containing formulations such as FLOSEAL or TISSEAL, either alone, or loaded with a fibrosis-inhibiting (or gliosis-inhibiting) agent, applied to the implantation site (or the implant/device surface); (d) hyaluronic acid- containing formulation
  • a preferred polymeric matrix which can be used to help prevent the formation of fibrous or gliotic tissue around the CRM or neuroimplant, either alone or in combination with a fibrosis (or gliosis) inhibiting agent/composition is formed from reactants comprising either one or both of pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl] (4-armed thiol PEG, which includes structures having a linking group(s) between a sulfhydryl group(s) and the terminus of the polyethylene glycol backbone) and pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG, which again includes structures having a linking group(s) between a NHS group(s) and the terminus of the polyethylene glycol backbone) as reactive reagents.
  • reactants comprising either one or both of pentaerythritol poly(ethylene glycol)ether te
  • Another preferred composition comprises either one or both of pentaerythritol poly(ethylene glycol)ether tetra-amino] (4-armed amino PEG, which includes structures having a linking group(s) between an amino group(s) and the terminus of the polyethylene glycol backbone) and pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG, which again includes structures having a linking group(s) between a NHS group(s) and the terminus of the polyethylene glycol backbone) as reactive reagents.
  • Chemical structures for these reactants are shown in, e.g., U.S. Patent 5,874,500.
  • collagen or a collagen derivative is added to the poly( ethylene glycol)-containing reactant(s) to form a preferred crosslinked matrix that can serve as a polymeric carrier for a therapeutic agent or a stand-alone composition to help prevent the formation of fibrous or gliotic tissue around the CRM or neuroimplant.
  • collagen or a collagen derivative e.g., methylated collagen
  • fibrosis-inhibiting (or gliosis- inhibiting) agents may be admixed with, blended with, conjugated to, or, otherwise modified to contain a polymer composition (which may be either biodegradable or non-biodegradable), or a non-polymeric composition, in order to release the therapeutic agent over a prolonged period of time.
  • a polymer composition which may be either biodegradable or non-biodegradable
  • a non-polymeric composition in order to release the therapeutic agent over a prolonged period of time.
  • localized delivery as well as localized sustained delivery of the fibrosis-inhibiting (or gliosis-inhibiting) agent may be required.
  • a desired fibrosis-inhibiting (or gliosis-inhibiting) agent may be admixed with, blended with, conjugated to, or otherwise modified to contain a polymeric composition (which may be either biodegradable or non- biodegradable), or non-polymeric composition, in order to release the fibrosis- inhibiting (or gliosis-inhibiting) agent over a period of time.
  • a polymeric composition which may be either biodegradable or non- biodegradable
  • the polymer composition may include a bioerodible or biodegradable polymer.
  • biodegradable polymer compositions suitable for the delivery of fibrosis-inhibiting (or gliosis-inhibiting) agents include albumin, collagen, gelatin, hyaluronic acid, starch, cellulose and cellulose derivatives (e.g., methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropylmethylcellulose phthalate), casein, dextrans, polysaccharides, fibrinogen, poly(ether ester) multiblock copolymers, based on poly( ethylene glycol) and poly(butylene terephthalate), tyrosine-derived polycarbonates (e.g., U.S.
  • Patent No. 6,120,491 poly(hydroxyl acids), poly(D,L-lactide), poly(D,L-lactide-co-glycolide), poly(glycolide), poly(hydroxybutyrate), polydioxanone, poly(alkylcarbonate) and poly(orthoesters), degradable polyesters (e.g., polyesters comprising the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, ⁇ -decanolactone, ⁇ -decanolactone, trimethylene carbonate, 1 ,4- dioxane-2-one or 1 ,5-dioxepan-2one.), poly(hydroxyvaleric acid), polydioxanone,
  • non-degradable polymers suitable for the delivery of fibrosis-inhibiting (or gliosis-inhibiting) agents include poly(ethylene-co-vinyl acetate) ("EVA") copolymers, silicone rubber, acrylic polymers (polyacrylic acid, polymethylacrylic acid, polymethylmethacrylate, poly(butyl methacrylate)), poly(alkylcynoacrylate) (e.g., poly(ethylcyanoacrylate), poly(butylcyanoacrylate) poly(hexylcyanoacrylate) poly(octylcyanoacrylate)), polyethylene, polypropylene, polyamides (nylon 6,6), polyurethanes (e.g., CHRONOFLEX AR and CHRONOFLEX AL (both from CardioTech International, Inc., Woburn, MA), BIONATE (Polymer Technology Group, Inc., Emergyville, CA), and PELLETHANE (Dow Chemical Company, Midland, Ml)), poly(ethylene
  • Polymers may also be developed which are either anionic (e.g., alginate, carrageenan, carboxymethyl cellulose, poly(acrylamido-2-methyl propane sulfonic acid) and copolymers thereof, poly(methacrylic acid and copolymers thereof and poly(acrylic acid) and copolymers thereof, as well as blends thereof, or cationic (e.g., chitosan, poly- L-lysine, polyethylenimine, and poly(allyl amine)) and blends thereof (see generally, Dunn et al., J. Applied Polymer Sci. 50:353-365, 1993; Cascone et al., J.
  • anionic e.g., alginate, carrageenan, carboxymethyl cellulose, poly(acrylamido-2-methyl propane sulfonic acid) and copolymers thereof, poly(methacrylic acid and copolymers thereof and poly(acrylic acid) and copolymers thereof, as well as
  • Particularly preferred polymeric carriers include poly(ethylene-co- vinyl acetate), polyurethanes (e.g., CHRONOFLEX AR, CHRONOFLEX AL, BIONATE, PELLETHANE), poly (D,L-lactic acid) oligomers and polymers, poly (L-lactic acid) oligomers and polymers, poly (glycolic acid), copolymers of lactic acid and glycolic acid, poly (caprolactone), poly (valerolactone), polyanhydrides, copolymers of poly (caprolactone) or poly (lactic acid) with a polyethylene glycol (e.g., MePEG), silicone rubbers, nitrocellulose, poly(styrene)block-poly(isobutylene)-block-poly(styrene), poly(acrylate) polymers and blends, admixtures, or co-polymers of any of the above.
  • polyurethanes e.g., CHRONOFLEX AR, CHRONO
  • polysaccharides such as hyaluronic acid, chitosan and fucans, and copolymers of polysaccharides with degradable polymers.
  • Other representative polymers capable of sustained localized delivery of fibrosis-inhibiting (or gliosis-inhibiting) agents include carboxylic polymers, polyacetates, polyacrylamides, polycarbonates, polyethers, polyesters, polyethylenes, polyvinylbutyrals, polysilanes, polyureas, polyurethanes, polyurethanes (e.g., CHRONOFLEX AR, CHRONOFLEX AL, BIONATE, AND PELLETHANE), polyoxides, polystyrenes, polysulfides, polysulfones, polysulfonides, polyvinylhalides, pyrrolidones, rubbers, thermal- setting polymers, cross-linkable acrylic and methacryl
  • all or a portion of the device is coated with a primer (bonding) layer and a drug release layer, as described in U.S. Patent application entitled, "Stent with Medicated Multi-Layer Hybrid Polymer Coating," filed September 16, 2003 (U.S. Serial No. 10/662,877).
  • a primer bonding
  • a drug release layer as described in U.S. Patent application entitled, "Stent with Medicated Multi-Layer Hybrid Polymer Coating,” filed September 16, 2003 (U.S. Serial No. 10/662,877).
  • the active agents can be imbibed into a surface hybrid polymer layer, or incorporated directly into the hybrid polymer coating solutions.
  • Imbibing drugs into surface polymer layers is an efficient method for evaluating polymer-drug performance in the laboratory, but for commercial production it may be preferred for the polymer and drug to be premixed in the casting mixture. Greater efficacy can be achieved by combining the two elements in the coating mixtures in order to control the ratio of active agent to polymer in the coatings. Such ratios are important parameters to the final properties of the medicated layers, i.e., they allow for better control of active agent concentration and duration of pharmacological activity.
  • Typical polymers used in the drug-release system can include water-insoluble cellulose esters, various polyurethane polymers including hydrophilic and hydrophobic versions, hydrophilic polymers such as polyethylene glycol (PEG), polyethylene oxide (PEO), polyvinylpyrrolidone (PVP), PVP copolymers such as vinyl acetate, hydroxyethyl methacrylate (HEMA) and copolymers such as methylmethacrylate (PMMA-HEMA), and other hydrophilic and hydrophobic acrylate polymers and copolymers containing functional groups such as carboxyl and/or hydroxyl.
  • hydrophilic polymers such as polyethylene glycol (PEG), polyethylene oxide (PEO), polyvinylpyrrolidone (PVP), PVP copolymers such as vinyl acetate, hydroxyethyl methacrylate (HEMA) and copolymers such as methylmethacrylate (PMMA-HEMA), and other hydrophilic and hydrophobic acrylate polymers
  • Cellulose esters such as cellulose acetate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, and cellulose nitrate may be used.
  • the therapeutic agent is formulated with a cellulose ester.
  • Cellulose nitrate is a preferred cellulose ester because of its compatibility with the active agents and its ability to impart non-tackiness and cohesiveness to the coatings.
  • Cellulose nitrate has been shown to stabilize entrapped drugs in ambient and processing conditions.
  • Various viscosity grades may be used in order to provide proper rheological properties when combined with the coating solids used in these formulations. Higher or lower viscosity grades can be used. However, the higher viscosity grades can be more difficult to use because of their higher viscosities. Thus, the lower viscosity grades, such as 3.5, 0.5 or 0.25 seconds, are generally preferred. Physical properties such as tensile strength, elongation, flexibility, and softening point are related to viscosity (molecular weight) and can decrease with the lower molecular weight species, especially below the 0.25 second grades.
  • the cellulose derivatives comprise hydroglucose structures.
  • Cellulose nitrate is a hydrophobic, water-insoluble polymer, and has high water resistance properties. This structure leads to high compatibility with many active agents, accounting for the high degree of stabilization provided to drugs entrapped in cellulose nitrate.
  • the structure of nitrocellulose is given below:
  • the therapeutic agent is formulated with two or more polymers before being associated with the electrical device.
  • the agent is formulated with both polyurethane ((e.g., CHRONOFLEX AR, CHRONOFLEX AL, BIONATE, and PELLETHANE) and cellulose nitrate to provide a hybrid polymer drug loaded matrix.
  • Polyurethanes provide the hybrid polymer matrix with greater flexibility and adhesion to the electrical device, particularly when the connector has been pre-coated with a primer. Polyurethanes can also be used to slow or hasten the drug elution from coatings. Aliphatic, aromatic, polytetramethylene ether glycol, and polycarbonate are among the types of polyurethanes, which can be used in the coatings.
  • an anti- scarring agent e.g., paclitaxel
  • a heparin complex such as benzalkonium heparinate or tridodecylammonium heparinate), may optionally be included in the formulation.
  • the electrical device is associated with a formulation that includes therapeutic agent, cellulose ester, and a polyurethane that is water-insoluble, flexible, and compatible with the cellulose ester.
  • a formulation that includes therapeutic agent, cellulose ester, and a polyurethane that is water-insoluble, flexible, and compatible with the cellulose ester.
  • Polyvinylpyrrolidone is a polyamide that possesses unusual complexing and colloidal properties and is essentially physiologically inert. PVP and other hydrophilic polymers are typically biocompatible. PVP may be incorporated into drug loaded hybrid polymer compositions in order to increase drug release rates. In one embodiment, the concentration of PVP that is used in drug loaded hybrid polymer compositions can be less than 20%. This concentration can not make the layers bioerodable or lubricious. In general, PVP concentrations from ⁇ 1 % to greater than 80% are deemed workable. In one aspect of the invention, the therapeutic agent that is associated with a electrical device is formulated with a PVP polymer.
  • the device is associated with a composition that comprises a anti-scarring agent as described above, and an acrylate polymer or copolymer.
  • polymeric carriers may be fashioned to release a fibrosis-inhibiting (or gliosis-inhibiting) agent upon exposure to a specific triggering event such as pH (see, e.g., Heller et al., "Chemically Self-Regulated Drug Delivery Systems," in Polymers in Medicine III, Elsevier Science Publishers B.V., Amsterdam, 1988, pp. 175-188; Kang et al., J. Applied Polymer Sci. 48:343-354, 1993; Dong et al., J. Controlled Release 19:171-178, 1992; Dong and Hoffman, J. Controlled Release 75:141- 152, 1991 ; Kim et al., J.
  • pH-sensitive polymers include poly(acrylic acid) and its derivatives (including for example, homopolymers such as poly(aminocarboxylic acid); poly(acrylic acid); poly(methyl acrylic acid), copolymers of such homopolymers, and copolymers of poly(acrylic acid) and/or acrylate or acrylamide Imonomers such as those discussed above.
  • pH sensitive polymers include polysaccharides such as cellulose acetate phthalate; hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose acetate succinate; cellulose acetate trimellilate; and chitosan.
  • pH sensitive polymers include any mixture of a pH sensitive polymer and a water-soluble polymer.
  • fibrosis-inhibiting (or gliosis-inhibiting) agents can be delivered via polymeric carriers which are temperature sensitive (see, e.g., Chen et al., "Novel Hydrogels of a Temperature-Sensitive PLURONIC Grafted to a Bioadhesive Polyacrylic Acid Backbone for Vaginal Drug Delivery," in Proceed. Intern. Symp.
  • thermogelling polymers and their gelatin temperature (LCST (°C)
  • LCST gelatin temperature
  • homopolymers such as poly(N-methyl-N-n-propylacrylamide), 19.8; poly(N-n-propylacrylamide), 21.5; poly(N-methyl-N-isopropylacrylamide), 22.3; poly(N-n-propylmethacrylamide), 28.0; poly(N-isopropylacrylamide), 30.9; poly(N, n-diethylacrylamide), 32.0; poly(N-isopropylmethacrylamide), 44.0; poly(N-cyclopropylacrylamide), 45.5; poly(N-ethylmethyacrylamide), 50.0; poly(N-methyl-N-ethylacrylamide), 56.0
  • thermogelling polymers may be made by preparing copolymers between (among) monomers of the above, or by combining such homopolymers with other water-soluble polymers such as acrylmonomers (e.g., acrylic acid and derivatives thereof, such as methylacrylic acid, acrylate monomers and derivatives thereof, such as butyl methacrylate, butyl acrylate, lauryl acrylate, and acrylamide monomers and derivatives thereof, such as N-butyl acrylamide and acrylamide).
  • acrylmonomers e.g., acrylic acid and derivatives thereof, such as methylacrylic acid, acrylate monomers and derivatives thereof, such as butyl methacrylate, butyl acrylate, lauryl acrylate, and acrylamide monomers and derivatives thereof, such as N-butyl acrylamide and acrylamide.
  • thermogelling polymers include cellulose ether derivatives such as hydroxypropyl cellulose, 41 °C; methyl cellulose, 55°C; hydroxypropylmethyl cellulose, 66°C; and ethylhydroxyethyl cellulose, polyalkylene oxide-polyester block copolymers of the structure X-Y, Y-X-Y and X-Y-X where X in a polyalkylene oxide and Y is a biodegradable polyester (e.g., PLG-PEG-PLG) and PLURONICs such as F-127, 10 - 15°C; L-122, 19°C; L-92, 26°C; L-81 , 20°C; and L-61 , 24°C.
  • PLG-PEG-PLG biodegradable polyester
  • PLURONICs such as F-127, 10 - 15°C; L-122, 19°C; L-92, 26°C; L-81 , 20°C; and L-61
  • patents relating to thermally gelling polymers and their preparation include U.S. Patent Nos. 6,451 ,346; 6,201 ,072; 6,117,949; 6,004,573; 5,702,717; and 5,484,610 and PCT Publication Nos. WO 99/07343; WO 99/18142; WO 03/17972; WO 01/82970; WO 00/18821 ; WO 97/15287; WO 01/41735; WO 00/00222 and WO 00/38651.
  • Fibrosis-inhibiting (or gliosis-inhibiting) agents may be linked by occlusion in the matrices of the polymer, bound by covalent linkages, or encapsulated in microcapsules.
  • therapeutic compositions are provided in non-capsular formulations such as microspheres (ranging from nanometers to micrometers in size), pastes, threads of various size, films and sprays.
  • therapeutic compositions may be fashioned into particles having any size ranging from 50 nm to 500 ⁇ m, depending upon the particular use. These compositions can be in the form of microspheres, microparticles and/or nanoparticles.
  • compositions can be formed by spray-drying methods, milling methods, coacervation methods, W/O emulsion methods, W/O/W emulsion methods, and solvent evaporation methods.
  • these compositions can include microemulsions, emulsions, liposomes and micelles.
  • such compositions may also be readily applied as a "spray", which solidifies into a film or coating for use as a device/implant surface coating or to line the tissues of the implantation site.
  • Such sprays may be prepared from microspheres of a wide array of sizes, including for example, from 0.1 ⁇ m to 3 ⁇ m, from 10 ⁇ m to 30 ⁇ m, and from 30 ⁇ m to 100 ⁇ m.
  • compositions of the present invention may also be prepared in a variety of paste or gel forms.
  • therapeutic compositions are provided which are liquid at one temperature (e.g., temperature greater than 37°C, such as 40°C, 45°C, 50°C, 55°C or 60°C), and solid or semi-solid at another temperature (e.g., ambient body temperature, or any temperature lower than 37°C).
  • temperature greater than 37°C such as 40°C, 45°C, 50°C, 55°C or 60°C
  • solid or semi-solid at another temperature e.g., ambient body temperature, or any temperature lower than 37°C.
  • Such "thermopastes” may be readily made utilizing a variety of techniques (see, e.g., PCT Publication WO 98/24427).
  • the therapeutic compositions of the present invention may be formed as a film or tube. These films or tubes can be porous or non-porous. Such films or tubes are generally less than 5, 4, 3, 2, or 1 mm thick, or less than 0.75 mm, or less than 0.5 mm, or less than 0.25 mm, or, less than 0.10 mm thick.
  • Films or tubes can also be generated of thicknesses less than 50 ⁇ m, 25 ⁇ m or 10 ⁇ m. Such films may be flexible with a good tensile strength (e.g., greater than 50, or greater than 100, or greater than 150 or 200 N/cm 2 ), good adhesive properties (i.e., adheres to moist or wet surfaces), and have controlled permeability. Fibrosis-inhibiting agents contained in polymeric films are particularly useful for application to the surface of a device or implant as well as to the surface of tissue, cavity or an organ.
  • polymeric carriers are provided which are adapted to contain and release a hydrophobic fibrosis- inhibiting (or gliosis-inhibiting) compound, and/or the carrier containing the hydrophobic compound in combination with a carbohydrate, protein or polypeptide.
  • the polymeric carrier contains or comprises regions, pockets, or granules of one or more hydrophobic compounds.
  • hydrophobic compounds may be incorporated within a matrix which contains the hydrophobic fibrosis-inhibiting (or gliosis-inhibiting) compound, followed by incorporation of the matrix within the polymeric carrier.
  • matrices can be utilized in this regard, including for example, carbohydrates and polysaccharides such as starch, cellulose, dextran, methylcellulose, sodium alginate, heparin, chitosan, hyaluronic acid, proteins or polypeptides such as albumin, collagen and gelatin.
  • hydrophobic compounds may be contained within a hydrophobic core, and this core contained within a hydrophilic shell.
  • Other carriers that may likewise be utilized to contain and deliver fibrosis-inhibiting (or gliosis-inhibiting) agents described herein include: hydroxypropyl cyclodextrin (Cserhati and Hollo, Int. J. Pharm.
  • liposomes see, e.g., Sharma et al., Cancer Res. 53:5877-5881 , 1993; Sharma and Straubinger, Pharm. Res. 7(60):889-896, 1994; WO 93/18751 ; U.S. Patent No. 5,242,073), liposome/gel (WO 94/26254), nanocapsules (Bartoli et al., J. Microencapsulation 7(2):191-197, 1990), micelles (Alkan-Onyuksel et al., Pharm. Res. 77(2):206-212, 1994), implants (Jampel et al., Invest. Ophthalm. Vis.
  • polymeric carriers can be materials that are formed in situ.
  • the precursors can be monomers or macromers that contain unsaturated groups that can be polymerized and/or cross-linked.
  • the monomers or macromers can then, for example, be injected into the treatment area or onto the surface of the treatment area and polymerized in situ using a radiation source (e.g., visible light, UV light) or a free radical system (e.g., potassium persulfate and ascorbic acid or iron and hydrogen peroxide).
  • a radiation source e.g., visible light, UV light
  • a free radical system e.g., potassium persulfate and ascorbic acid or iron and hydrogen peroxide.
  • the polymerization step can be performed immediately prior to, simultaneously to or post injection of the reagents into the treatment site.
  • Representative examples of compositions that undergo free radical polymerization reactions are described in WO 01/44307, WO 01/68720, WO 02/072166, WO 03/043552, WO 93/17669, WO 00/64977, U.S. Patent Nos.
  • the present invention provides for polymeric crosslinked matrices, and polymeric carriers, that may be used to assist in the prevention of the formation or growth of fibrous connective tissue or glial tissue.
  • the composition may contain and deliver fibrosis-inhibiting (or gliosis-inhibiting) agents in the vicinity of the medical device.
  • the following compositions are particularly useful when it is desired to infiltrate around the device, with or without a fibrosis-inhibiting agent.
  • Such polymeric materials may be prepared from, e.g., (a) synthetic materials, (b) naturally-occurring materials, or (c) mixtures of synthetic and naturally occurring materials.
  • the matrix may be prepared from, e.g., (a) a one-component, i.e., self-reactive, compound, or (b) two or more compounds that are reactive with one another.
  • these materials are fluid prior to delivery, and thus can be sprayed or otherwise extruded from a device in order to deliver the composition. After delivery, the component materials react with each other, and/or with the body, to provide the desired affect.
  • materials that are reactive with one another must be kept separated prior to delivery to the patient, and are mixed together just prior to being delivered to the patient, in order that they maintain a fluid form prior to delivery.
  • the components of the matrix are delivered in a liquid state to the desired site in the body, whereupon in situ polymerization occurs.
  • crosslinked polymer compositions are prepared by reacting a first synthetic polymer containing two or more nucleophilic groups with a second synthetic polymer containing two or more electrophilic groups, where the electrophilic groups are capable of covalently binding with the nucleophilic groups.
  • the first and second polymers are each non-immunogenic.
  • the matrices are not susceptible to enzymatic cleavage by, e.g., a matrix metalloproteinase (e.g., collagenase) and are therefore expected to have greater long-term persistence in vivo than collagen-based compositions.
  • polymer refers inter alia to polyalkyls, polyamino acids, polyalkyleneoxides and polysaccharides. Additionally, for external or oral use, the polymer may be polyacrylic acid or carbopol.
  • synthetic polymer refers to polymers that are not naturally occurring and that are produced via chemical synthesis. As such, naturally occurring proteins such as collagen and naturally occurring polysaccharides such as hyaluronic acid are specifically excluded. Synthetic collagen, and synthetic hyaluronic acid, and their derivatives, are included.
  • Multifunctionally activated synthetic polymers Synthetic polymers containing either nucleophilic or electrophilic groups are also referred to herein as "multifunctionally activated synthetic polymers.”
  • multifunctionally activated refers to synthetic polymers which have, or have been chemically modified to have, two or more nucleophilic or electrophilic groups which are capable of reacting with one another (i.e., the nucleophilic groups react with the electrophilic groups) to form covalent bonds.
  • Types of multifunctionally activated synthetic polymers include difunctionally activated, tetrafunctionally activated, and star-branched polymers.
  • Multifunctionally activated synthetic polymers for use in the present invention must contain at least two, more preferably, at least three, functional groups in order to form a three-dimensional crosslinked network with synthetic polymers containing multiple nucleophilic groups (i.e., "multi- nucleophilic polymers"). In other words, they must be at least difunctionally activated, and are more preferably trifunctionally or tetrafunctionally activated. If the first synthetic polymer is a difunctionally activated synthetic polymer, the second synthetic polymer must contain three or more functional groups in order to obtain a three-dimensional crosslinked network. Most preferably, both the first and the second synthetic polymer contain at least three functional groups.
  • Multi-nucleophilic polymers Synthetic polymers containing multiple nucleophilic groups are also referred to generically herein as "multi-nucleophilic polymers.”
  • multi-nucleophilic polymers must contain at least two, more preferably, at least three, nucleophilic groups. If a synthetic polymer containing only two nucleophilic groups is used, a synthetic polymer containing three or more electrophilic groups must be used in order to obtain a three- dimensional crosslinked network.
  • Preferred multi-nucleophilic polymers for use in the compositions and methods of the present invention include synthetic polymers that contain, or have been modified to contain, multiple nucleophilic groups such as primary amino groups and thiol groups.
  • Preferred multi-nucleophilic polymers include: (i) synthetic polypeptides that have been synthesized to contain two or more primary amino groups or thiol groups; and (ii) polyethylene glycols that have been modified to contain two or more primary amino groups or thiol groups.
  • reaction of a thiol group with an electrophilic group tends to proceed more slowly than reaction of a primary amino group with an electrophilic group.
  • the multi-nucleophilic polypeptide is a synthetic polypeptide that has been synthesized to incorporate amino acid residues containing primary amino groups (such as lysine) and/or amino acids containing thiol groups (such as cysteine).
  • Poly(lysine)s have been prepared having anywhere from 6 to about 4,000 primary amino groups, corresponding to molecular weights of about 870 to about 580,000.
  • Poly(lysine)s for use in the present invention preferably have a molecular weight within the range of about 1 ,000 to about 300,000; more preferably, within the range of about 5,000 to about 100,000; most preferably, within the range of about 8,000 to about 15,000.
  • Poly(lysine)s of varying molecular weights are commercially available from Peninsula Laboratories, Inc. (Belmont, Calif.) and Aldrich Chemical (Milwaukee, WI).
  • Polyethylene glycol can be chemically modified to contain multiple primary amino or thiol groups according to methods set forth, for example, in Chapter 22 of Poly(ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, J. Milton Harris, ed., Plenum Press, N.Y. (1992). Polyethylene glycols which have been modified to contain two or more primary amino groups are referred to herein as "multi-amino PEGs.” Polyethylene glycols which have been modified to contain two or more thiol groups are referred to herein as "multi-thiol PEGs.” As used herein, the term "polyethylene glycol(s)" includes modified and or derivatized polyethylene glycol(s).
  • Multi-amino PEGs useful in the present invention include Huntsman's Jeffamine diamines ("D” series) and triamines ("T” series), which contain two and three primary amino groups per molecule, respectively.
  • Polyamines such as ethylenediamine (H 2 N-CH 2 -CH 2 -NH 2 ), tetramethylenediamine (H 2 N-(CH 2 ) 4 -NH 2 ), pentamethylenediamine (cadaverine) (H 2 N-(CH 2 )5-NH2), hexamethylenediamine (H 2 N-(CH 2 )6-NH 2 ), di(2- aminoethyl)amine (HN-(CH2-CH 2 -NH 2 )2), and tris(2-aminoethyl)amine (N-(CH 2 - CH -NH 2 ) 3 ) may also be used as the synthetic polymer containing multiple nucleophilic groups.
  • ethylenediamine H 2 N-CH 2 -CH 2 -NH 2
  • tetramethylenediamine H 2 N-(CH 2 ) 4 -NH 2
  • pentamethylenediamine cadaverine
  • H 2 N-(CH 2 )5-NH2
  • Multi-electrophilic polymers Synthetic polymers containing multiple electrophilic groups are also referred to herein as "multi-electrophilic polymers.”
  • the multifunctionally activated synthetic polymers must contain at least two, more preferably, at least three, electrophilic groups in order to form a three-dimensional crosslinked network with multi-nucleophilic polymers.
  • Preferred multi-electrophilic polymers for use in the compositions of the invention are polymers which contain two or more succinimidyl groups capable of forming covalent bonds with nucleophilic groups on other molecules. Succinimidyl groups are highly reactive with materials containing primary amino (NH 2 ) groups, such as multi-amino PEG, poly(lysine), or collagen.
  • Succinimidyl groups are slightly less reactive with materials containing thiol (SH) groups, such as multi-thiol PEG or synthetic polypeptides containing multiple cysteine residues.
  • thiol (SH) groups such as multi-thiol PEG or synthetic polypeptides containing multiple cysteine residues.
  • the term "containing two or more succinimidyl groups” is meant to encompass polymers which are preferably commercially available containing two or more succinimidyl groups, as well as those that must be chemically derivatized to contain two or more succinimidyl groups.
  • succinimidyl group is intended to encompass sulfosuccinimidyl groups and other such variations of the "generic" succinimidyl group.
  • PEG refers to polymers having the repeating structure (OCH 2 -CH 2 ) n . Structures for some specific, tetrafunctionally activated forms of PEG are shown in FIGS. 4 to 13 of U.S. Patent 5,874,500, incorporated herein by reference.
  • PEGS include PEG succinimidyl propionate (SE-PEG), PEG succinimidyl succinamide (SSA-PEG), and PEG succinimidyl carbonate (SC-PEG).
  • SE-PEG PEG succinimidyl propionate
  • SSA-PEG PEG succinimidyl succinamide
  • SC-PEG PEG succinimidyl carbonate
  • the crosslinked matrix is formed in situ by reacting pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl] (4-armed thiol PEG) and pentaerythritol poly( ethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG) as reactive reagents. Structures for these reactants are shown in U.S. Patent 5,874,500.
  • Each of these materials has a core with a structure that may be seen by adding ethylene oxide-derived residues to each of the hydroxyl groups in pentaerythritol, and then derivatizing the terminal hydroxyl groups (derived from the ethylene oxide) to contain either thiol groups (so as to form 4-armed thiol PEG) or N-hydroxysuccinimydyl groups (so as to form 4-armed NHS
  • PEG polyethylene glycol
  • a linker group present between the ethylene oxide derived backbone and the reactive functional group, where this product is commercially available as COSEAL from Angiotech Pharmaceuticals Inc.
  • a group "D” may be present in one or both of these molecules, as discussed in more detail below.
  • preferred activated polyethylene glycol derivatives for use in the invention contain succinimidyl groups as the reactive group. However, different activating groups can be attached at sites along the length of the PEG molecule.
  • PEG can be derivatized to form functionally activated PEG propionaldehyde (A-PEG), or functionally activated PEG glycidyl ether (E-PEG), or functionally activated PEG-isocyanate (l-PEG), or functionally activated PEG-vinylsulfone (V-PEG).
  • Hydrophobic polymers can also be used to prepare the compositions of the present invention.
  • Hydrophobic polymers for use in the present invention preferably contain, or can be derivatized to contain, two or more electrophilic groups, such as succinimidyl groups, most preferably, two, three, or four electrophilic groups.
  • hydrophobic polymer refers to polymers which contain a relatively small proportion of oxygen or nitrogen atoms.
  • Hydrophobic polymers which already contain two or more succinimidyl groups include, without limitation, disuccinimidyl suberate (DSS), bis(sulfosuccinimidyl) suberate (BS3), dithiobis(succinimidylpropionate) (DSP), bis(2-succinimidooxycarbonyloxy) ethyl sulfone (BSOCOES), and 3,3'- dithiobis(sulfosuccinimidylpropionate (DTSPP), and their analogs and derivatives.
  • DSS disuccinimidyl suberate
  • BS3 bis(sulfosuccinimidyl) suberate
  • DSP dithiobis(succinimidylpropionate)
  • BSOCOES bis(2-succinimidooxycarbonyloxy) ethyl
  • Preferred hydrophobic polymers for use in the invention generally have a carbon chain that is no longer than about 14 carbons.
  • Polymers having carbon chains substantially longer than 14 carbons generally have very poor solubility in aqueous solutions and, as such, have very long reaction times when mixed with aqueous solutions of synthetic polymers containing multiple nucleophilic groups.
  • Certain polymers, such as polyacids, can be derivatized to contain two or more functional groups, such as succinimidyl groups.
  • Polyacids for use in the present invention include, without limitation, trimethylolpropane-based tricarboxylic acid, di(trimethylol propane)-based tetracarboxylic acid, heptanedioic acid, octanedioic acid (suberic acid), and hexadecanedioic acid (thapsic acid). Many of these polyacids are commercially available from DuPont Chemical Company (Wilmington, DE).
  • polyacids can be chemically derivatized to contain two or more succinimidyl groups by reaction with an appropriate molar amount of N-hydroxysuccinimide (NHS) in the presence of N,N'-dicyclohexylcarbodiimide (DCC).
  • NHS N-hydroxysuccinimide
  • DCC N,N'-dicyclohexylcarbodiimide
  • Polyalcohols such as trimethylolpropane and di(trimethylol propane) can be converted to carboxylic acid form using various methods, then further derivatized by reaction with NHS in the presence of DCC to produce trifunctionally and tetrafunctionally activated polymers, respectively, as described in U.S. Application Ser. No. 08/403,358.
  • Polyacids such as heptanedioic acid (HOOC-(CH 2 ) 5 -COOH), octanedioic acid (HOOC-(CH 2 ) 6 - COOH), and hexadecanedioic acid (HOOC-(CH 2 ) ⁇ 4 -COOH) are derivatized by the addition of succinimidyl groups to produce difunctionally activated polymers.
  • Polyamines such as ethylenediamine, tetramethylenediamine, pentamethylenediamine (cadaverine), hexamethylenediamine, bis (2- aminoethyl)amine, and tris(2-aminoethyl)amine can be chemically derivatized to polyacids, which can then be derivatized to contain two or more succinimidyl groups by reacting with the appropriate molar amounts of N- hydroxysuccinimide in the presence of DCC, as described in U.S. Application Ser. No. 08/403,358. Many of these polyamines are commercially available from DuPont Chemical Company.
  • X and Y may be the same or different, i.e., a synthetic polymer may have two different electrophilic groups, or two different nucleophilic groups, such as with glutathione.
  • the backbone of at least one of the synthetic polymers comprises alkylene oxide residues, e.g., residues from ethylene oxide, propylene oxide, and mixtures thereof.
  • the term 'backbone' refers to a significant portion of the polymer.
  • the synthetic polymer containing alkylene oxide residues may be described by the formula X-polymer-X or Y-polymer-Y, wherein X and Y are as defined above, and the term "polymer” represents - (CH2CH2 O) n - or -(CH(CH 3 )CH 2 0) n - or -(CH 2 -CH 2 -0)n-(CH(CH 3 )CH2-0)n-. In these cases the synthetic polymer would be difunctional.
  • the required functional group X or Y is commonly coupled to the polymer backbone by a linking group (represented below as "Q"), many of which are known or possible.
  • Q groups include -0-(CH 2 ) n -; -S-(CH 2 ) n -; -NH-(CH 2 ) n -; -0 2 C-NH-(CH 2 ) n -; -0 2 C-(CH 2 ) n -; -0 2 C-(CR 1 H) n -; and -0-R 2 -CO-NH-, which provide synthetic polymers of the partial structures: polymer-0-(CH 2 ) n -(X or Y); polymer-S-(CH 2 )n-(X or Y); polymer-NH-(CH 2 ) n -(X or Y); polymer-0 2 C-NH- (CH 2 )n-(X or Y); polymer-0 2 C-NH- (CH 2 )n-(X or Y); polymer-0 2 C-
  • n 1-10
  • R 1 H or alkyl (i.e., CH 3 , C 2 H 5 , etc.);
  • R 2 CH 2 , or CO-NH-CH 2 CH 2 ; and Q 1 and Q 2 may be the same or different.
  • D An additional group, represented below as "D" can be inserted between the polymer and the linking group, if present.
  • D group One purpose of such a D group is to affect the degradation rate of the crosslinked polymer composition in vivo, for example, to increase the degradation rate, or to decrease the degradation rate. This may be useful in many instances, for example, when drug has been incorporated into the matrix, and it is desired to increase or decrease polymer degradation rate so as to influence a drug delivery profile in the desired direction.
  • An illustration of a crosslinking reaction involving first and second synthetic polymers each having D and Q groups is shown below.
  • Some useful biodegradable groups "D" include polymers formed from one or more ⁇ -hydroxy acids, e.g., lactic acid, glycolic acid, and the cyclization products thereof (e.g., lactide, glycolide), ⁇ -caprolactone, and amino acids.
  • the polymers may be referred to as polylactide, polyglycolide, poly(co- lactide-glycolide); poly- ⁇ -caprolactone, polypeptide (also known as poly amino acid, for example, various di- or tri-peptides) and poly(anhydride)s.
  • a first synthetic polymer containing multiple nucleophilic groups is mixed with a second synthetic polymer containing multiple electrophilic groups. Formation of a three-dimensional crosslinked network occurs as a result of the reaction between the nucleophilic groups on the first synthetic polymer and the electrophilic groups on the second synthetic polymer.
  • concentrations of the first synthetic polymer and the second synthetic polymer used to prepare the compositions of the present invention will vary depending upon a number of factors, including the types and molecular weights of the particular synthetic polymers used and the desired end use application.
  • multi-amino PEG as the first synthetic polymer, it is preferably used at a concentration in the range of about 0.5 to about 20 percent by weight of the final composition, while the second synthetic polymer is used at a concentration in the range of about 0.5 to about 20 percent by weight of the final composition.
  • a final composition having a total weight of 1 gram (1000 milligrams) would contain between about 5 to about 200 milligrams of multi-amino PEG, and between about 5 to about 200 milligrams of the second synthetic polymer.
  • Use of higher concentrations of both first and second synthetic polymers will result in the formation of a more tightly crosslinked network, producing a stiffer, more robust gel.
  • compositions intended for use in tissue augmentation will generally employ concentrations of first and second synthetic polymer that fall toward the higher end of the preferred concentration range.
  • Compositions intended for use as bioadhesives or in adhesion prevention do not need to be as firm and may therefore contain lower polymer concentrations.
  • the second synthetic polymer is generally stored and used in sterile, dry form to prevent the loss of crosslinking ability due to hydrolysis which typically occurs upon exposure of such electrophilic groups to aqueous media. Processes for preparing synthetic hydrophilic polymers containing multiple electrophylic groups in sterile, dry form are set forth in U.S. Patent 5,643,464.
  • the dry synthetic polymer may be compression molded into a thin sheet or membrane, which can then be sterilized using gamma or, preferably, e-beam irradiation.
  • the resulting dry membrane or sheet can be cut to the desired size or chopped into smaller size particulates.
  • polymers containing multiple nucleophilic groups are generally not water-reactive and can therefore be stored in aqueous solution.
  • one or both of the electrophilic- or nucleophilic-terminated polymers described above can be combined with a synthetic or naturally occurring polymer. The presence of the synthetic or naturally occurring polymer may enhance the mechanical and/or adhesive properties of the in situ forming compositions.
  • Naturally occurring polymers, and polymers derived from naturally occurring polymer that may be included in in situ forming materials include naturally occurring proteins, such as collagen, collagen derivatives (such as methylated collagen), fibrinogen, thrombin, albumin, fibrin, and derivatives of and naturally occurring polysaccharides, such as glycosaminoglycans, including deacetylated and desulfated glycosaminoglycan derivatives.
  • a composition comprising naturally-occurring protein and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising collagen and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising methylated collagen and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising fibrinogen and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising thrombin and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising albumin and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising fibrin and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising naturally occurring polysaccharide and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising glycosaminoglycan and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising deacetylated glycosaminoglycan and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising desulfated glycosaminoglycan and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising naturally-occurring protein and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising collagen and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising methylated collagen and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising fibrinogen and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising thrombin and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention
  • a composition comprising albumin and the first synthetic polyme r as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising fibrin and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising naturally occurring polysaccharide and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising glycosaminoglycan and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising deacetylated glycosaminoglycan and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising desulfated glycosaminoglycan and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising naturally-occurring protein and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising collagen and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising methylated collagen and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising fibrinogen and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising thrombin and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising albumin and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising fibrin and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising naturally occurring polysaccharide and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising glycosaminoglycan and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising deacetylated glycosaminoglycan and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising desulfated glycosaminoglycan and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • protein or polysaccharide components which contain functional groups that can react with the functional groups on multiple activated synthetic polymers can result in formation of a crosslinked synthetic polymer-naturally occurring polymer matrix upon mixing and/or crosslinking of the synthetic polymer(s).
  • the naturally occurring polymer protein or polysaccharide
  • the electrophilic groups on the second synthetic polymer will react with the primary amino groups on these components, as well as the nucleophilic groups on the first synthetic polymer, to cause these other components to become part of the polymer matrix.
  • lysine-rich proteins such as collagen may be especially reactive with electrophilic groups on synthetic polymers.
  • the naturally occurring protein is polymer may be collagen.
  • collagen refers to all forms of collagen, including those which have been processed or otherwise modified and is intended to encompass collagen of any type, from any source, including, but not limited to, collagen extracted from tissue or produced recombinantly, collagen analogues, collagen derivatives, modified collagens, and denatured collagens, such as gelatin.
  • collagen from any source may be included in the compositions of the invention; for example, collagen may be extracted and purified from human or other mammalian source, such as bovine or porcine corium and human placenta, or may be recombinantly or otherwise produced.
  • the preparation of purified, substantially non-antigenic collagen in solution from bovine skin is well known in the art. U.S.
  • Patent No. 5,428,022 discloses methods of extracting and purifying collagen from the human placenta.
  • U.S. Patent No. 5,667,839 discloses methods of producing recombinant human collagen in the milk of transgenic animals, including transgenic cows.
  • Collagen of any type including, but not limited to, types I, II, III, IV, or any combination thereof, may be used in the compositions of the invention, although type I is generally preferred.
  • Either atelopeptide or telopeptide-containing collagen may be used; however, when collagen from a xenogeneic source, such as bovine collagen, is used, atelopeptide collagen is generally preferred, because of its reduced immunogenicity compared to telopeptide-containing collagen.
  • Collagen that has not been previously crosslinked by methods such as heat, irradiation, or chemical crosslinking agents is preferred for use in the compositions of the invention, although previously crosslinked collagen may be used.
  • Non-crosslinked atelopeptide fibrillar collagen is commercially available from Inamed Aesthetics (Santa Barbara, CA) at collagen concentrations of 35 mg/ml and 65 mg/ml under the trademarks ZYDERM I Collagen and ZYDERM II Collagen, respectively.
  • Glutaraldehyde crosslinked atelopeptide fibrillar collagen is commercially available from Inamed Corporation (Santa Barbara, CA) at a collagen concentration of 35 mg/ml under the trademark ZYPLAST Collagen.
  • Collagens for use in the present invention are generally in aqueous suspension at a concentration between about 20 mg/ml to about 120 mg/ml; preferably, between about 30 mg/ml to about 90 mg/ml. Because of its tacky consistency, nonfibrillar collagen may be preferred for use in compositions that are intended for use as bioadhesives.
  • nonfibrillar collagen refers to any modified or unmodified collagen material that is in substantially nonfibrillar form at pH 7, as indicated by optical clarity of an aqueous suspension of the collagen. Collagen that is already in nonfibrillar form may be used in the compositions of the invention.
  • nonfibrillar collagen is intended to encompass collagen types that are nonfibrillar in native form, as well as collagens that have been chemically modified such that they are in nonfibrillar form at or around neutral pH.
  • Collagen types that are nonfibrillar (or microfibrillar) in native form include types IV, VI, and VII.
  • Chemically modified collagens that are in nonfibrillar form at neutral pH include succinylated collagen and methylated collagen, both of which can be prepared according to the methods described in U.S. Pat. No. 4,164,559, issued Aug. 14, 1979, to Miyata et al., which is hereby incorporated by reference in its entirety.
  • methylated collagen is particularly preferred for use in bioadhesive compositions, as disclosed in U.S. Application Ser. No. 08/476,825.
  • Collagens for use in the crosslinked polymer compositions of the present invention may start out in fibrillar form, then be rendered nonfibrillar by the addition of one or more fiber disassembly agent.
  • the fiber disassembly agent must be present in an amount sufficient to render the collagen substantially nonfibrillar at pH 7, as described above.
  • Fiber disassembly agents for use in the present invention include, without limitation, various biocompatible alcohols, amino acids (e.g., arginine), inorganic salts (e.g., sodium chloride and potassium chloride), and carbohydrates (e.g., various sugars including sucrose).
  • the polymer may be collagen or a collagen derivative, for example methylated collagen.
  • an in situ forming composition uses pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl] (4- armed thiol PEG), pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG) and methylated collagen as the reactive reagents.
  • This composition when mixed with the appropriate buffers can produce a crosslinked hydrogel.
  • the naturally occurring polymer may be a glycosaminoglycan.
  • Glycosaminoglycans e.g., hyaluronic acid
  • the glycosaminoglycan may be derivatized.
  • glycosaminoglycans can be chemically derivatized by, e.g., deacetylation, desulfation, or both in order to contain primary amino groups available for reaction with electrophilic groups on synthetic polymer molecules.
  • Glycosaminoglycans that can be derivatized according to either or both of the aforementioned methods include the following: hyaluronic acid, chondroitin sulfate A, chondroitin sulfate B (dermatan sulfate), chondroitin sulfate C, chitin (can be derivatized to chitosan), keratan sulfate, keratosulfate, and heparin.
  • Derivatization of glycosaminoglycans by deacetylation and/or desulfation and covalent binding of the resulting glycosaminoglycan derivatives with synthetic hydrophilic polymers is described in further detail in commonly assigned, allowed U.S.
  • the collagen is added to the first synthetic polymer, then the collagen and first synthetic polymer are mixed thoroughly to achieve a homogeneous composition.
  • the second synthetic polymer is then added and mixed into the collagen/first synthetic polymer mixture, where it will covalently bind to primary amino groups or thiol groups on the first synthetic polymer and primary amino groups on the collagen, resulting in the formation of a homogeneous crosslinked network.
  • Various deacetylated and/or desulfated glycosaminoglycan derivatives can be incorporated into the composition in a similar manner as that described above for collagen.
  • the introduction of hydrocolloids such as carboxymethylcellulose may promote tissue adhesion and/or swellability.
  • compositions of the present invention having two synthetic polymers may be administered before, during or after crosslinking of the first and second synthetic polymer.
  • the point at which crosslinking has reached equilibrium is defined herein as the point at which the composition no longer feels tacky or sticky to the touch.
  • the first synthetic polymer and second synthetic polymer may be contained within separate barrels of a dual-compartment syringe.
  • the two synthetic polymers do not actually mix until the point at which the two polymers are extruded from the tip of the syringe needle into the patient's tissue.
  • This allows the vast majority of the crosslinking reaction to occur in situ, avoiding the problem of needle blockage which commonly occurs if the two synthetic polymers are mixed too early and crosslinking between the two components is already too advanced prior to delivery from the syringe needle.
  • the use of a dual-compartment syringe, as described above, allows for the use of smaller diameter needles, which is advantageous when performing soft tissue augmentation in delicate facial tissue, such as that surrounding the eyes.
  • first synthetic polymer and second synthetic polymer may be mixed according to the methods described above prior to delivery to the tissue site, then injected to the desired tissue site immediately (preferably, within about 60 seconds) following mixing.
  • first synthetic polymer and second synthetic polymer are mixed, then extruded and allowed to crosslink into a sheet or other solid form. The crosslinked solid is then dehydrated to remove substantially all unbound water.
  • the resulting dried solid may be ground or comminuted into particulates, then suspended in a nonaqueous fluid carrier, including, without limitation, hyaluronic acid, dextran sulfate, dextran, succinylated noncrosslinked collagen, methylated noncrosslinked collagen, glycogen, glycerol, dextrose, maltose, triglycerides of fatty acids (such as corn oil, soybean oil, and sesame oil), and egg yolk phospholipid.
  • a nonaqueous fluid carrier including, without limitation, hyaluronic acid, dextran sulfate, dextran, succinylated noncrosslinked collagen, methylated noncrosslinked collagen, glycogen, glycerol, dextrose, maltose, triglycerides of fatty acids (such as corn oil, soybean oil, and sesame oil), and egg yolk phospholipid.
  • the suspension of particulates can be injected through a small- gauge needle to a tissue site
  • the first and/or second synthetic polymers may be combined with a hydrophilic polymer, e.g., collagen or methylated collagen, to form a composition useful in the present invention.
  • a hydrophilic polymer e.g., collagen or methylated collagen
  • the compositions useful in the present invention include a hydrophilic polymer in combination with two or more crosslinkable components. This embodiment is described in further detail in this section.
  • the hydrophilic Polymer component may be a synthetic or naturally occurring hydrophilic polymer.
  • Naturally occurring hydrophilic polymers include, but are not limited to: proteins such as collagen and derivatives thereof, fibronectin, albumins, globulins, fibrinogen, and fibrin, with collagen particularly preferred; carboxylated polysaccharides such as polymannuronic acid and polygalacturonic acid; aminated polysaccharides, particularly the glycosaminoglycans, e.g., hyaluronic acid, chitin, chondroitin sulfate A, B, or C, keratin sulfate, keratosulfate and heparin; and activated polysaccharides such as dextran and starch derivatives.
  • Collagen e.g., methylated collagen
  • glycosaminoglycans are preferred naturally occurring hydrophilic polymers for use herein.
  • collagen from any source may be used in the composition of the method; for example, collagen may be extracted and purified from human or other mammalian source, such as bovine or porcine corium and human placenta, or may be recombinantly or otherwise produced.
  • the preparation of purified, substantially non-antigenic collagen in solution from bovine skin is well known in the art. See, e.g., U.S. Pat. No. 5,428,022, to Palefsky et al., which discloses methods of extracting and purifying collagen from the human placenta. See also U.S. Patent No.
  • collagen or "collagen material” as used herein refers to all forms of collagen, including those that have been processed or otherwise modified.
  • Collagen of any type including, but not limited to, types I, II, III, IV, or any combination thereof, may be used in the compositions of the invention, although type I is generally preferred.
  • Either atelopeptide or telopeptide- containing collagen may be used; however, when collagen from a source, such as bovine collagen, is used, atelopeptide collagen is generally preferred, because of its reduced immunogenicity compared to telopeptide-containing collagen.
  • Collagen that has not been previously crosslinked by methods such as heat, irradiation, or chemical crosslinking agents is preferred for use in the compositions of the invention, although previously crosslinked collagen may be used.
  • Non-crosslinked atelopeptide fibrillar collagen is commercially available from McGhan Medical Corporation (Santa Barbara, Calif.) at collagen concentrations of 35 mg/ml and 65 mg/ml under the trademarks ZYDERM ® I Collagen and ZYDERM ® II Collagen, respectively.
  • Glutaraldehyde-crosslinked atelopeptide fibrillar collagen is commercially available from McGhan Medical Corporation at a collagen concentration of 35 mg/ml under the trademark ZYPLAST ® .
  • Collagens for use in the present invention are generally, although not necessarily, in aqueous suspension at a concentration between about 20 mg/ml to about 120 mg/ml, preferably between about 30 mg/ml to about 90 mg/ml.
  • intact collagen is preferred, denatured collagen, commonly known as gelatin, can also be used in the compositions of the invention. Gelatin may have the added benefit of being degradable faster than collagen. Because of its greater surface area and greater concentration of reactive groups, nonfibrillar collagen is generally preferred.
  • nonfibrillar collagen refers to any modified or unmodified collagen material that is in substantially nonfibrillar form at pH 7, as indicated by optical clarity of an aqueous suspension of the collagen.
  • Collagen that is already in nonfibrillar form may be used in the compositions of the invention.
  • nonfibrillar collagen is intended to encompass collagen types that are nonfibrillar in native form, as well as collagens that have been chemically modified such that they are in nonfibrillar form at or around neutral pH.
  • Collagen types that are nonfibrillar (or microfibrillar) in native form include types IV, VI, and VII.
  • Chemically modified collagens that are in nonfibrillar form at neutral pH include succinylated collagen, propylated collagen, ethylated collagen, methylated collagen, and the like, both of which can be prepared according to the methods described in U.S. Pat. No.
  • Collagens for use in the crosslinkable compositions of the present invention may start out in fibrillar form, then be rendered nonfibrillar by the addition of one or more fiber disassembly agents.
  • the fiber disassembly agent must be present in an amount sufficient to render the collagen substantially nonfibrillar at pH 7, as described above.
  • Fiber disassembly agents for use in the present invention include, without limitation, various biocompatible alcohols, amino acids, inorganic salts, and carbohydrates, with biocompatible alcohols being particularly preferred.
  • Preferred biocompatible alcohols include glycerol and propylene glycol.
  • Non-biocompatible alcohols such as ethanol, methanol, and isopropanol, are not preferred for use in the present invention, due to their potentially deleterious effects on the body of the patient receiving them.
  • Preferred amino acids include arginine.
  • Preferred inorganic salts include sodium chloride and potassium chloride.
  • carbohydrates such as various sugars including sucrose
  • they are not as preferred as other types of fiber disassembly agents because they can have cytotoxic effects in vivo.
  • fibrillar collagen has less surface area and a lower concentration of reactive groups than nonfibrillar, fibrillar collagen is less preferred.
  • fibrillar collagen, or mixtures of nonfibrillar and fibrillar collagen may be preferred for use in compositions intended for long-term persistence in vivo, if optical clarity is not a requirement.
  • Synthetic hydrophilic polymers may also be used in the present invention.
  • Useful synthetic hydrophilic polymers include, but are not limited to: polyalkylene oxides, particularly polyethylene glycol and poly( ethylene oxide)- poly(propylene oxide) copolymers, including block and random copolymers; polyols such as glycerol, polyglycerol (particularly highly branched polyglycerol), propylene glycol and trimethylene glycol substituted with one or more polyalkylene oxides, e.g., mono-, di- and tri-polyoxyethylated glycerol, mono- and di-polyoxyethylated propylene glycol, and mono- and di- polyoxyethylated trimethylene glycol; polyoxyethylated sorbitol, polyoxyethylated glucose; acrylic acid polymers and analogs and copolymers thereof, such as polyacrylic acid per se, polymethacrylic acid, poly(hydroxyethyl-methacrylate), poly(hydroxyethylacrylate), poly(methylalky
  • the compositions of the invention also comprise a plurality of crosslinkable components.
  • Each of the crosslinkable components participates in a reaction that results in a crosslinked matrix.
  • the crosslinkable components Prior to completion of the crosslinking reaction, the crosslinkable components provide the necessary adhesive qualities that enable the methods of the invention.
  • the crosslinkable components are selected so that crosslinking gives rise to a biocompatible, nonimmunogenic matrix useful in a variety of contexts including adhesion prevention, biologically active agent delivery, tissue augmentation, and other applications.
  • the crosslinkable components of the invention comprise: a component A, which has m nucleophilic groups, wherein m > 2 and a component B, which has n electrophilic groups capable of reaction with the m nucleophilic groups, wherein n > 2 and m + n > 4.
  • An optional third component, optional component C, which has at least one functional group that is either electrophilic and capable of reaction with the nucleophilic groups of component A, or nucleophilic and capable of reaction with the electrophilic groups of component B may also be present.
  • the total number of functional groups present on components A, B and C, when present, in combination is > 5; that is, the total functional groups given by m + n + p must be > 5, where p is the number of functional groups on component C and, as indicated, is > 1.
  • Each of the components is biocompatible and nonimmunogenic, and at least one component is comprised of a hydrophilic polymer.
  • the composition may contain additional crosslinkable components D, E, F, etc., having one or more reactive nucleophilic or electrophilic groups and thereby participate in formation of the crosslinked biomaterial via covalent bonding to other components.
  • the m nucleophilic groups on component A may all be the same, or, alternatively, A may contain two or more different nucleophilic groups.
  • the n electrophilic groups on component B may all be the same, or two or more different electrophilic groups may be present.
  • the functional group(s) on optional component C if nucleophilic, may or may not be the same as the nucleophilic groups on component A, and, conversely, if electrophilic, the functional group(s) on optional component C may or may not be the same as the electrophilic groups on component B.
  • the components may be represented by the structural formulae (I) R 1 (-[Q 1 ] q -X) m (component A), (II) R 2 (-[Q 2 ] r -Y)n (component B), and (III) R 3 (-[Q 3 ] s -Fn) p (optional component C), wherein: R 1 , R 2 and R 3 are independently selected from the group consisting of C 2 to C- ⁇ 4 hydrocarbyl, heteroatom-containing C 2 to C-
  • Reactive Groups may be virtually any nucleophilic group, so long as reaction can occur with the electrophilic group Y.
  • Y may be virtually any electrophilic group, so long as reaction can take place with X.
  • the only limitation is a practical one, in that reaction between X and Y should be fairly rapid and take place automatically upon admixture with an aqueous medium, without need for heat or potentially toxic or non-biodegradable reaction catalysts or other chemical reagents. It is also preferred although not essential that reaction occur without need for ultraviolet or other radiation.
  • the reactions between X and Y should be complete in under 60 minutes, preferably under 30 minutes. Most preferably, the reaction occurs in about 5 to 15 minutes or less.
  • nucleophilic groups suitable as X include, but are not limited to, -NH 2 , -NHR 4 , -N(R 4 ) 2 , -SH, -OH, -COOH, -C 6 H 4 -OH, -PH 2 , -PHR 5 , - P(R 5 ) 2 , -NH-NH 2 , -CO-NH-NH 2 , -C 5 H 4 N, etc.
  • R 4 and R 5 are hydrocarbyl, typically alkyl or monocyclic aryl, preferably alkyl, and most preferably lower alkyl.
  • Organometallic moieties are also useful nucleophilic groups for the purposes of the invention, particularly those that act as carbanion donors.
  • Organometallic nucleophiles are not, however, preferred.
  • organometallic moieties include: Grignard functionalities -R 6 MgHal wherein R 6 is a carbon atom (substituted or unsubstituted), and Hal is halo, typically bromo, iodo or chloro, preferably bromo; and lithium-containing functionalities, typically alkyllithium groups; sodium-containing functionalities. It will be appreciated by those of ordinary skill in the art that certain nucleophilic groups must be activated with a base so as to be capable of reaction with an electrophile.
  • the composition when there are nucleophilic sulfhydryl and hydroxyl groups in the crosslinkable composition, the composition must be admixed with an aqueous base in order to remove a proton and provide an -S " or -O " species to enable reaction with an electrophile.
  • a nonnucleophilic base is preferred.
  • the base may be present as a component of a buffer solution. Suitable bases and corresponding crosslinking reactions are described infra. The selection of electrophilic groups provided within the crosslinkable composition, i.e., on component B, must be made so that reaction is possible with the specific nucleophilic groups.
  • the Y groups are selected so as to react with amino groups.
  • the X moieties are sulfhydryl moieties
  • the corresponding electrophilic groups are sulfhydryl-reactive groups, and the like.
  • a carboxylic acid group per se is not susceptible to reaction with a nucleophilic amine
  • components containing carboxylic acid groups must be activated so as to be amine-reactive. Activation may be accomplished in a variety of ways, but often involves reaction with a suitable hydroxyl-containing compound in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or dicyclohexylurea (DHU).
  • a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or dicyclohexylurea (DHU).
  • a carboxylic acid can be reacted with an alkoxy-substituted N- hydroxy-succinimide or N-hydroxysulfosuccinimide in the presence of DCC to form reactive electrophilic groups, the N-hydroxysuccinimide ester and the N- hydroxysulfosuccinimide ester, respectively.
  • Carboxylic acids may also be activated by reaction with an acyl halide such as an acyl chloride (e.g., acetyl chloride), to provide a reactive anhydride group.
  • a carboxylic acid may be converted to an acid chloride group using, e.g., thionyl chloride or an acyl chloride capable of an exchange reaction.
  • thionyl chloride or an acyl chloride capable of an exchange reaction Specific reagents and procedures used to carry out such activation reactions will be known to those of ordinary skill in the art and are described in the pertinent texts and literature.
  • the electrophilic groups present on Y are groups that react with a sulfhydryl moiety.
  • Such reactive groups include those that form thioester linkages upon reaction with a sulfhydryl group, such as those described in PCT Publication No. WO 00/62827 to Wallace et al.
  • such "sulfhydryl reactive" groups include, but are not limited to: mixed anhydrides; ester derivatives of phosphorus; ester derivatives of p-nitrophenol, p-nitrothiophenol and pentafluorophenol; esters of substituted hydroxylamines, including N-hydroxyphthalimide esters, N- hydroxysuccinimide esters, N-hydroxysulfosuccinimide esters, and N- hydroxyglutarimide esters; esters of 1-hydroxybenzotriazole; 3-hydroxy-3,4- dihydro-benzotriazin-4-one; 3-hydroxy-3,4-dihydro-quinazoline-4-one; carbonylimidazole derivatives; acid chlorides; ketenes; and isocyanates.
  • auxiliary reagents can also be used to facilitate bond formation, e.g., 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide can be used to facilitate coupling of sulfhydryl groups to carboxyl-containing groups.
  • sulfhydryl reactive groups that form thioester linkages various other sulfhydryl reactive functionalities can be utilized that form other types of linkages. For example, compounds that contain methyl imidate derivatives form imido-thioester linkages with sulfhydryl groups.
  • sulfhydryl reactive groups can be employed that form disulfide bonds with sulfhydryl groups; such groups generally have the structure -S-S-Ar where Ar is a substituted or unsubstituted nitrogen-containing heteroaromatic moiety or a non-heterocyclic aromatic group substituted with an electron- withdrawing moiety, such that Ar may be, for example, 4-pyridinyl, o- nitrophenyl, m-nitrophenyl, p-nitrophenyl, 2,4-dinitrophenyl, 2-nitro-4-benzoic acid, 2-nitro-4-pyridinyl, etc.
  • auxiliary reagents i.e., mild oxidizing agents such as hydrogen peroxide
  • sulfhydryl reactive groups forms thioether bonds with sulfhydryl groups.
  • groups include, inter alia, maleimido, substituted maleimido, haloalkyl, epoxy, imino, and aziridino, as well as olefins (including conjugated olefins) such as ethenesulfonyl, etheneimino, acrylate, methacrylate, and ⁇ , ⁇ -unsaturated aldehydes and ketones.
  • This class of sulfhydryl reactive groups are particularly preferred as the thioether bonds may provide faster crosslinking and longer in vivo stability.
  • the electrophilic functional groups on the remaining component(s) must react with hydroxyl groups.
  • the hydroxyl group may be activated as described above with respect to carboxylic acid groups, or it may react directly in the presence of base with a sufficiently reactive electrophile such as an epoxide group, an aziridine group, an acyl halide, or an anhydride.
  • suitable electrophilic functional groups for reaction therewith are those containing carbonyl groups, including, by way of example, ketones and aldehydes. It will also be appreciated that certain functional groups can react as nucleophiles or as electrophiles, depending on the selected reaction partner and/or the reaction conditions.
  • a carboxylic acid group can act as a nucleophile in the presence of a fairly strong base, but generally acts as an electrophile allowing nucleophilic attack at the carbonyl carbon and concomitant replacement of the hydroxyl group with the incoming nucleophile.
  • covalent linkages in the crosslinked structure that result upon covalent binding of specific nucleophilic components to specific electrophilic components in the crosslinkable composition include, solely by way of example, the following (the optional linking groups Q 1 and Q 2 are omitted for clarity):
  • Linking Groups The functional groups X and Y and FN on optional component C may be directly attached to the compound core (R 1 , R 2 or R 3 on optional component C, respectively), or they may be indirectly attached through a linking group, with longer linking groups also termed "chain extenders.”
  • chain extenders In structural formulae (I), (II) and (III), the optional linking groups are represented by Q 1 , Q 2 and Q 3 , wherein the linking groups are present when q, r and s are equal to 1 (with R, X, Y, Fn, m n and p as defined previously). Suitable linking groups are well known in the art. See, for example, International Patent Publication No. WO 97/22371.
  • Linking groups are useful to avoid steric hindrance problems that are sometimes associated with the formation of direct linkages between molecules.
  • Linking groups may additionally be used to link several multifunctionally activated compounds together to make larger molecules.
  • a linking group can be used to alter the degradative properties of the compositions after administration and resultant gel formation.
  • linking groups can be incorporated into components A, B, or optional component C to promote hydrolysis, to discourage hydrolysis, or to provide a site for enzymatic degradation.
  • linking groups that provide hydrolyzable sites, include, inter alia: ester linkages; anhydride linkages, such as obtained by incorporation of glutarate and succinate; ortho ester linkages; ortho carbonate linkages such as trimethylene carbonate; amide linkages; phosphoester linkages; ⁇ -hydroxy acid linkages, such as may be obtained by incorporation of lactic acid and glycolic acid; lactone-based linkages, such as may be obtained by incorporation of caprolactone, valerolactone, ⁇ -butyrolactone and p- dioxanone; and amide linkages such as in a dimeric, oligomeric, or poly(amino acid) segment.
  • non-degradable linking groups include succinimide, propionic acid and carboxymethylate linkages. See, for example, PCT WO 99/07417.
  • enzymatically degradable linkages include Leu-Gly-Pro-Ala, which is degraded by collagenase; and Gly-Pro-Lys, which is degraded by plasmin.
  • Linking groups can also enhance or suppress the reactivity of the various nucleophilic and electrophilic groups. For example, electron- withdrawing groups within one or two carbons of a sulfhydryl group would be expected to diminish its effectiveness in coupling, due to a lowering of nucleophilicity. Carbon-carbon double bonds and carbonyl groups will also have such an effect.
  • n is generally in the range of 1 to about 10
  • R 7 is generally hydrocarbyl, typically alkyl or aryl, preferably alkyl, and most preferably lower alkyl
  • R 8 is hydrocarbylene, heteroatom-containing hydrocarbylene, substituted hydrocarbylene, or substituted heteroatom- containing hydrocarbylene) typically alkylene or arylene (again, optionally substituted and/or containing a heteroatom), preferably lower alkylene (e.g., methylene, ethylene, n-propylene, n-butylene, etc.), phenylene, or amidoalkylene (e.g., -(CO)-NH-CH 2 ).
  • lower alkylene e.g., methylene, ethylene, n-propylene, n-butylene, etc.
  • phenylene or amidoalkylene (e.g., -(CO)-NH-CH 2 ).
  • linking groups are as follows: If higher molecular weight components are to be used, they preferably have biodegradable linkages as described above, so that fragments larger than 20,000 mol. wt. are not generated during resorption in the body. In addition, to promote water miscibility and/or solubility, it may be desired to add sufficient electric charge or hydrophilicity. Hydrophilic groups can be easily introduced using known chemical synthesis, so long as they do not give rise to unwanted swelling or an undesirable decrease in compressive strength. In particular, polyalkoxy segments may weaken gel strength.
  • the Component Core The "core" of each crosslinkable component is comprised of the molecular structure to which the nucleophilic or electrophilic groups are bound.
  • the "core” groups are R 1 , R 2 and R 3 .
  • Each molecular core of the reactive components of the crosslinkable composition is generally selected from synthetic and naturally occurring hydrophilic polymers, hydrophobic polymers, and C 2 -C ⁇ hydrocarbyl groups zero to 2 heteroatoms selected from N, O and S, with the proviso that at least one of the crosslinkable components A, B, and optionally C, comprises a molecular core of a synthetic hydrophilic polymer.
  • at least one of A and B comprises a molecular core of a synthetic hydrophilic polymer.
  • the crosslinkable component(s) is (are) hydrophilic polymers.
  • hydrophilic polymer refers to a synthetic polymer having an average molecular weight and composition effective to render the polymer "hydrophilic" as defined above.
  • synthetic crosslinkable hydrophilic polymers useful herein include, but are not limited to: polyalkylene oxides, particularly polyethylene glycol and poly( ethylene oxide)-poly(propylene oxide) copolymers, including block and random copolymers; polyols such as glycerol, polyglycerol (particularly highly branched polyglycerol), propylene glycol and trimethylene glycol substituted with one or more polyalkylene oxides, e.g., mono-, di- and tri-polyoxyethylated glycerol, mono- and di-polyoxyethylated propylene glycol, and mono- and di- polyoxyethylated trimethylene glycol; polyoxyethylated sorbitol, polyoxyethylated glucose; acrylic acid polymers and analogs and copolymers thereof, such as polyacrylic acid per se, polymethacrylic acid, poly(hydroxyethyl-methacrylate), poly(hydroxyethyl)
  • the synthetic crosslinkable hydrophilic polymer may be a homopolymer, a block copolymer, a random copolymer, or a graft copolymer.
  • the polymer may be linear or branched, and if branched, may be minimally to highly branched, dendrimeric, hyperbranched, or a star polymer.
  • the polymer may include biodegradable segments and blocks, either distributed throughout the polymer's molecular structure or present as a single block, as in a block copolymer.
  • Biodegradable segments are those that degrade so as to break covalent bonds. Typically, biodegradable segments are segments that are hydrolyzed in the presence of water and/or enzymatically cleaved in situ. Biodegradable segments may be composed of small molecular segments such as ester linkages, anhydride linkages, ortho ester linkages, ortho carbonate linkages, amide linkages, phosphonate linkages, etc. Larger biodegradable "blocks" will generally be composed of oligomeric or polymeric segments incorporated within the hydrophilic polymer.
  • Illustrative oligomeric and polymeric segments that are biodegradable include, by way of example, poly(amino acid) segments, poly(orthoester) segments, poly(orthocarbonate) segments, and the like.
  • Other suitable synthetic crosslinkable hydrophilic polymers include chemically synthesized polypeptides, particularly polynucleophilic polypeptides that have been synthesized to incorporate amino acids containing primary amino groups (such as lysine) and/or amino acids containing thiol groups (such as cysteine).
  • Poly(lysine) a synthetically produced polymer of the amino acid lysine (145 MW), is particularly preferred.
  • Poly(lysine)s have been prepared having anywhere from 6 to about 4,000 primary amino groups, corresponding to molecular weights of about 870 to about 580,000.
  • Poly(lysine)s for use in the present invention preferably have a molecular weight within the range of about 1 ,000 to about 300,000, more preferably within the range of about 5,000 to about 100,000, and most preferably, within the range of about 8,000 to about 15,000.
  • Poly(lysine)s of varying molecular weights are commercially available from Peninsula Laboratories, Inc. (Belmont, Calif.).
  • the synthetic crosslinkable hydrophilic polymer may be a homopolymer, a block copolymer, a random copolymer, or a graft copolymer.
  • the polymer may be linear or branched, and if branched, may be minimally to highly branched, dendrimeric, hyperbranched, or a star polymer.
  • the polymer may include biodegradable segments and blocks, either distributed throughout the polymer's molecular structure or present as a single block, as in a block copolymer.
  • Biodegradable segments are those that degrade so as to break covalent bonds.
  • biodegradable segments are segments that are hydrolyzed in the presence of water and/or enzymatically cleaved in situ.
  • Biodegradable segments may be composed of small molecular segments such as ester linkages, anhydride linkages, ortho ester linkages, ortho carbonate linkages, amide linkages, phosphonate linkages, etc.
  • Larger biodegradable "blocks" will generally be composed of oligomeric or polymeric segments incorporated within the hydrophilic polymer.
  • Illustrative oligomeric and polymeric segments that are biodegradable include, by way of example, poly(amino acid) segments, poly(orthoester) segments, poly(orthocarbonate) segments, and the like.
  • preferred synthetic crosslinkable hydrophilic polymers are polyethylene glycol (PEG) and polyglycerol (PG), particularly highly branched polyglycerol.
  • PEG polyethylene glycol
  • PG polyglycerol
  • Various forms of PEG are extensively used in the modification of biologically active molecules because PEG lacks toxicity, antigenicity, and immunogenicity (i.e., is biocompatible), can be formulated so as to have a wide range of solubilities, and do not typically interfere with the enzymatic activities and/or conformations of peptides.
  • a particularly preferred synthetic crosslinkable hydrophilic polymer for certain applications is a polyethylene glycol (PEG) having a molecular weight within the range of about 100 to about 100,000 mol. wt., although for highly branched PEG, far higher molecular weight polymers can be employed - up to 1 ,000,000 or more - providing that biodegradable sites are incorporated ensuring that all degradation products will have a molecular weight of less than about 30,000.
  • the preferred molecular weight is about 1 ,000 to about 20,000 mol. wt., more preferably within the range of about 7,500 to about 20,000 mol. wt.
  • the polyethylene glycol has a molecular weight of approximately 10,000 mol. wt.
  • Naturally occurring crosslinkable hydrophilic polymers include, but are not limited to: proteins such as collagen, fibronectin, albumins, globulins, fibrinogen, and fibrin, with collagen particularly preferred; carboxylated polysaccharides such as polymannuronic acid and polygalacturonic acid; aminated polysaccharides, particularly the glycosaminoglycans, e.g., hyaluronic acid, chitin, chondroitin sulfate A, B, or C, keratin sulfate, keratosulfate and heparin; and activated polysaccharides such as dextran and starch derivatives.
  • proteins such as collagen, fibronectin, albumins, globulins, fibrinogen, and fibrin, with collagen particularly preferred
  • carboxylated polysaccharides such as polymannuronic acid and polygalacturonic acid
  • aminated polysaccharides particularly the glycosaminoglycans
  • Collagen and glycosaminoglycans are examples of naturally occurring hydrophilic polymers for use herein, with methylated collagen being a preferred hydrophilic polymer.
  • Any of the hydrophilic polymers herein must contain, or be activated to contain, functional groups, i.e., nucleophilic or electrophilic groups, which enable crosslinking. Activation of PEG is discussed below; it is to be understood, however, that the following discussion is for purposes of illustration and analogous techniques may be employed with other polymers.
  • PEG first of all, various functionalized polyethylene glycols have been used effectively in fields such as protein modification (see Abuchowski et al., Enzymes as Drugs, John Wiley & Sons: New York, N.Y.
  • Activated forms of PEG including multifunctionally activated PEG, are commercially available, and are also easily prepared using known methods. For example, see Chapter 22 of Poly(ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, J. Milton Harris, ed., Plenum Press, NY (1992); and Shearwater Polymers, Inc. Catalog, Polyethylene Glycol Derivatives,
  • FIGS. 1 to 10 of U.S. Patent 5,874,500 structures for some specific, tetrafunctionally activated forms of PEG are shown in FIGS. 1 to 10 of U.S. Patent 5,874,500, as are generalized reaction products obtained by reacting the activated PEGs with multi-amino
  • PEGs i.e., a PEG with two or more primary amino groups.
  • the activated PEGs illustrated have a pentaerythritol (2,2-bis(hydroxymethyl)-1 ,3-propanediol) core.
  • Such activated PEGs are readily prepared by conversion of the exposed hydroxyl groups in the PEGylated polyol
  • the crosslinkable compositions of the invention can also include hydrophobic polymers, although for most uses hydrophilic polymers are preferred.
  • Polylactic acid and polyglycolic acid are examples of two hydrophobic polymers that can be used. With other hydrophobic polymers, only short-chain oligomers should be used, containing at most about 14 carbon atoms, to avoid solubility-related problems during reaction.
  • the molecular core of one or more of the crosslinkable components can also be a low molecular weight compound, i.e., a C 2 -Ci 4 hydrocarbyl group containing zero to 2 heteroatoms selected from N, O, S and combinations thereof.
  • a molecular core can be substituted with nucleophilic groups or with electrophilic groups.
  • the component may be, for example, ethylenediamine (H 2 N-CH 2 CH 2 -NH 2 ), tetramethylenediamine (H 2 N-(CH 4 )-NH 2 ), pentamethylenediamine (cadaverine) (H N-(CH 5 )-NH 2 ), hexamethylenediamine (H 2 N-(CH 6 )-NH 2 ), bis(2-aminoethyl)amine (HN-[CH 2 CH 2 -NH 2 ] 2 ), or tris(2- aminoethyl)amine (N-[CH 2 CH 2 -NH 2 ] 3 ).
  • ethylenediamine H 2 N-CH 2 CH 2 -NH 2
  • tetramethylenediamine H 2 N-(CH 4 )-NH 2
  • pentamethylenediamine cadaverine
  • H N-(CH 5 )-NH 2 hexamethylenediamine
  • H 2 N-(CH 6 )-NH 2 bis(2-amino
  • Low molecular weight diols and polyols include trimethylolpropane, di(trimethylol propane), pentaerythritol, and diglycerol, all of which require activation with a base in order to facilitate their reaction as nucleophiles.
  • Such diols and polyols may also be functionalized to provide di- and poly-carboxylic acids, functional groups that are, as noted earlier herein, also useful as nucleophiles under certain conditions.
  • Polyacids for use in the present compositions include, without limitation, trimethylolpropane-based tricarboxylic acid, di(trimethylol propane)-based tetracarboxylic acid, heptanedioic acid, octanedioic acid (suberic acid), and hexadecanedioic acid (thapsic acid), all of which are commercially available and/or readily synthesized using known techniques.
  • Low molecular weight di- and poly-electrophiles include, for example, disuccinimidyl suberate (DSS), bis(sulfosuccinimidyl) suberate (BS 3 ), dithiobis(succinimidylpropionate) (DSP), bis(2-succinimidooxycarbonyloxy) ethyl sulfone (BSOCOES), and 3,3'-dithiobis(sulfosuccinimidylpropionate (DTSPP), and their analogs and derivatives.
  • DSS disuccinimidyl suberate
  • BS 3 bis(sulfosuccinimidyl) suberate
  • DSP dithiobis(succinimidylpropionate)
  • BSOCOES bis(2-succinimidooxycarbonyloxy) ethyl sulfone
  • DTSPP 3,3'-dithiobis(sulfosuccin
  • di- and poly- electrophiles can also be synthesized from di- and polyacids, for example by reaction with an appropriate molar amount of N-hydroxysuccinimide in the presence of DCC.
  • Polyols such as trimethylolpropane and di(trimethylol propane) can be converted to carboxylic acid form using various known techniques, then further derivatized by reaction with NHS in the presence of DCC to produce trifunctionally and tetrafunctionally activated polymers.
  • Suitable delivery systems for the homogeneous dry powder composition (containing at least two crosslinkable polymers) and the two buffer solutions may involve a multi-compartment spray device, where one or more compartments contains the powder and one or more compartments contain the buffer solutions needed to provide for the aqueous environment, so that the composition is exposed to the aqueous environment as it leaves the compartment.
  • a multi-compartment spray device where one or more compartments contains the powder and one or more compartments contain the buffer solutions needed to provide for the aqueous environment, so that the composition is exposed to the aqueous environment as it leaves the compartment.
  • Many devices that are adapted for delivery of multi-component tissue sealants/hemostatic agents are well known in the art and can also be used in the practice of the present invention.
  • the composition can be delivered using any type of controllable extrusion system, or it can be delivered manually in the form of a dry powder, and exposed to the aqueous environment at the site of administration.
  • the homogeneous dry powder composition and the two buffer solutions may be conveniently formed under aseptic conditions by placing each of the three ingredients (dry powder, acidic buffer solution and basic buffer solution) into separate syringe barrels.
  • the composition, first buffer solution and second buffer solution can be housed separately in a multiple-compartment syringe system having a multiple barrels, a mixing head, and an exit orifice.
  • the first buffer solution can be added to the barrel housing the composition to dissolve the composition and form a homogeneous solution, which is then extruded into the mixing head.
  • the second buffer solution can be simultaneously extruded into the mixing head.
  • the resulting composition can then be extruded through the orifice onto a surface.
  • the syringe barrels holding the dry powder and the basic buffer may be part of a dual-syringe system, e.g., a double barrel syringe as described in U.S. Patent 4,359,049 to Redl et al.
  • the acid buffer can be added to the syringe barrel that also holds the dry powder, so as to produce the homogeneous solution.
  • the acid buffer may be added (e.g., injected) into the syringe barrel holding the dry powder to thereby produce a homogeneous solution of the first and second components. This homogeneous solution can then be extruded into a mixing head, while the basic buffer is simultaneously extruded into the mixing head.
  • the homogeneous solution and the basic buffer are mixed together to thereby form a reactive mixture.
  • the reactive mixture is extruded through an orifice and onto a surface (e.g., tissue), where a film is formed, which can function as a sealant or a barrier, or the like.
  • the reactive mixture begins forming a three-dimensional matrix immediately upon being formed by the mixing of the homogeneous solution and the basic buffer in the mixing head. Accordingly, the reactive mixture is preferably extruded from the mixing head onto the tissue very quickly after it is formed so that the three-dimensional matrix forms on, and is able to adhere to, the tissue.
  • Other systems for combining two reactive liquids are well known in the art, and include the systems described in U.S. Patent Nos.
  • the electrophilic component or components are generally stored and used in sterile, dry form to prevent hydrolysis.
  • Processes for preparing synthetic hydrophilic polymers containing multiple electrophilic groups in sterile, dry form are set forth in commonly assigned U.S. Patent No. 5,643,464 to Rhee et al.
  • the dry synthetic polymer may be compression molded into a thin sheet or membrane, which can then be sterilized using gamma or, preferably, e-beam irradiation. The resulting dry membrane or sheet can be cut to the desired size or chopped into smaller size particulates.
  • Components containing multiple nucleophilic groups are generally not water-reactive and can therefore be stored either dry or in aqueous solution. If stored as a dry, particulate, solid, the various components of the crosslinkable composition may be blended and stored in a single container. Admixture of all components with water, saline, or other aqueous media should not occur until immediately prior to use.
  • the crosslinking components can be mixed together in a single aqueous medium in which they are both unreactive, i.e., such as in a low pH buffer. Thereafter, they can be sprayed onto the targeted tissue site along with a high pH buffer, after which they will rapidly react and form a gel.
  • Suitable liquid media for storage of crosslinkable compositions include aqueous buffer solutions such as monobasic sodium phosphate/dibasic sodium phosphate, sodium carbonate/sodium bicarbonate, glutamate or acetate, at a concentration of 0.5 to 300 mM.
  • a sulfhydryl-reactive component such as PEG substituted with maleimido groups or succinimidyl esters is prepared in water or a dilute buffer, with a pH of between around 5 to 6.
  • Buffers with pKs between about 8 and 10.5 for preparing a polysulfhydryl component such as sulfhydryl-PEG are useful to achieve fast gelation time of compositions containing mixtures of sulfhydryl-PEG and SG-PEG.
  • These include carbonate, borate and AMPSO (3-[(1 ,1-dimethyl-2- hydroxyethyl)amino]2-hydroxy-propane-sulfonic acid).
  • a pH of around 5 to 9 is preferred for the liquid medium used to prepare the sulfhydryl PEG.
  • the polymer composition may include collagen in combination with fibrinogen and/or thrombin.
  • an aqueous composition may include a fibrinogen and FXIII, particularly plasma, collagen in an amount sufficient to thicken the composition, thrombin in an amount sufficient to catalyze polymerization of fibrinogen present in the composition, and Ca 2+ and, optionally, an antifibrinolytic agent in amount sufficient to retard degradation of the resulting adhesive clot.
  • the composition may be formulated as a two-part composition that may be mixed together just prior to use, in which fibrinogen/FXIII and collagen constitute the first component, and thrombin together with an antifibrinolytic agent, and Ca 2+ constitute the second component.
  • Plasma which provides a source of fibrinogen, may be obtained from the patient for which the composition is to be delivered.
  • the plasma can be used "as is” after standard preparation which includes centrifuging out cellular components of blood.
  • the plasma can be further processed to concentrate the fibrinogen to prepare a plasma cryoprecipitate.
  • the plasma cryoprecipitate can be prepared by freezing the plasma for at least about an hour at about -20°C, and then storing the frozen plasma overnight at about 4°C to slowly thaw.
  • the thawed plasma is centrifuged and the plasma cryoprecipitate is harvested by removing approximately four-fifths of the plasma to provide a cryoprecipitate comprising the remaining one-fifth of the plasma.
  • Other fibrinogen/FXIII preparations may be used, such as cryoprecipitate, patient autologous fibrin sealant, fibrinogen analogs or other single donor or commercial fibrin sealant materials.
  • Approximately 0.5 ml to about 1.0 ml of either the plasma or the plasma-cryoprecipitate provides about 1 to 2 ml of adhesive composition which is sufficient for use in middle ear surgery.
  • Plasma proteins may or may not be present in the fibrinogen/FXII separation due to wide variations in the formulations and methods to derive them.
  • Collagen preferably hypoallergenic collagen, is present in the composition in an amount sufficient to thicken the composition and augment the cohesive properties of the preparation.
  • the collagen may be atelopeptide collagen or telopeptide collagen, e.g., native collagen.
  • the collagen augments the fibrin by acting as a macromolecular lattice work or scaffold to which the fibrin network adsorbs.
  • the form of collagen which is employed may be described as at least "near native" in its structural characteristics. It may be further characterized as resulting in insoluble fibers at a pH above 5; unless crosslinked or as part of a complex composition, e.g., bone, it will generally consist of a minor amount by weight of fibers with diameters greater than 50 nm, usually from about 1 to 25 volume % and there will be substantially little, if any, change in the helical structure of the fibrils. In addition, the collagen composition must be able to enhance gelation in the surgical adhesion composition.
  • ZYDERM Collagen Implant has a fibrillar diameter distribution consisting of 5 to 10 nm diameter fibers at 90% volume content and the remaining 10 % with greater than about 50 nm diameter fibers.
  • ZCI is available as a fibrillar slurry and solution in phosphate buffered isotonic saline, pH 7.2, and is injectable with fine gauge needles.
  • cross-linked collagen available as ZYPLAST may be employed.
  • ZYPLAST is essentially an exogenously crosslinked (glutaraldehyde) version of ZCI. The material has a somewhat higher content of greater than about 50 nm diameter fibrils and remains insoluble over a wide pH range.
  • Crosslinking has the effect of mimicking in vivo endogenous crosslinking found in many tissues.
  • Thrombin acts as a catalyst for fibrinogen to provide fibrin, an insoluble polymer and is present in the composition in an amount sufficient to catalyze polymerization of fibrinogen present in the patient plasma.
  • Thrombin also activates FXIII, a plasma protein that catalyzes covalent crosslinks in fibrin, rendering the resultant clot insoluble.
  • the thrombin is present in the adhesive composition in concentration of from about 0.01 to about 1000 or greater NIH units (NIHu) of activity, usually about i to about 500 NIHu, most usually about 200 to about 500 NIHu.
  • the thrombin can be from a variety of host animal sources, conveniently bovine. Thrombin is commercially available from a variety of sources including Parke-Davis, usually lyophilized with buffer salts and stabilizers in vials which provide thrombin activity ranging from about 1000 NIHu to 10,000 NIHu.
  • the thrombin is usually prepared by reconstituting the powder by the addition of either sterile distilled water or isotonic saline. Alternately, thrombin analogs or reptile-sourced coagulants may be used.
  • the composition may additionally comprise an effective amount of an antifibrinolytic agent to enhance the integrity of the glue clot as the healing processes occur.
  • a number of antifibrinolytic agents are well known and include aprotinin, C1-esterase inhibitor and ⁇ -amino-n-caproic acid (EACA).
  • ⁇ - amino-n-caproic acid the only antifibrinolytic agent approved by the FDA, is effective at a concentration of from about 5 mg/ml to about 40 mg/ml of the final adhesive composition, more usually from about 20 to about 30 mg/ml.
  • EACA is commercially available as a solution having a concentration of about 250 mg/ml. Conveniently, the commercial solution is diluted with distilled water to provide a solution of the desired concentration. That solution is desirably used to reconstitute lyophilized thrombin to the desired thrombin concentration.
  • in situ forming materials based on the crosslinking of proteins are described, e.g., in U.S. Patent Nos. RE38158; 4,839,345; 5,514,379, 5,583,114; 6,458,147; 6,371 ,975; 5,290,552; 6,096,309; U.S. Patent Application Publication Nos. 2002/0161399; 2001/0018598 and PCT Publication Nos. WO 03/090683; WO 01/45761; WO 99/66964 and WO 96/03159).
  • the therapeutic agent is released from a crosslinked matrix formed, at least in part, from a self-reactive compound.
  • a self-reactive compound comprises a core substituted with a minimum of three reactive groups.
  • the reactive groups may be directed attached to the core of the compound, or the reactive groups may be indirectly attached to the compound's core, e.g., the reactive groups are joined to the core through one or more linking groups.
  • Each of the three reactive groups that are necessarily present in a self-reactive compound can undergo a bond-forming reaction with at least one of the remaining two reactive groups. For clarity it is mentioned that when these compounds react to form a crosslinked matrix, it will most often happen that reactive groups on one compound will reactive with reactive groups on another compound.
  • the term "self-reactive” is not intended to mean that each self-reactive compound necessarily reacts with itself, but rather that when a plurality of identical self-reactive compounds are in combination and undergo a crosslinking reaction, then these compounds will react with one another to form the matrix.
  • the compounds are "self-reactive” in the sense that they can react with other compounds having the identical chemical structure as themselves.
  • the self-reactive compound comprises at least four components: a core and three reactive groups.
  • the self-reactive compound can be characterized by the formula (I), where R is the core, the reactive groups are represented by X 1 , X 2 and X 3 , and a linker (L) is optionally present between the core and a functional group.
  • the core R is a polyvalent moiety having attachment to at least three groups (i.e., it is at least trivalent) and may be, or may contain, for example, a hydrophilic polymer, a hydrophobic polymer, an amphiphilic polymer, a C2-14 hydrocarbyl, or a C2-14 hydrocarbyl which is heteroatom- containing.
  • the linking groups L 1 , L 2 , and L 3 may be the same or different.
  • the designators p, q and r are either 0 (when no linker is present) or 1 (when a linker is present).
  • the reactive groups X 1 , X 2 and X 3 may be the same or different.
  • each of these reactive groups reacts with at least one other reactive group to form a three-dimensional matrix. Therefore X 1 can react with X 2 and/or X 3 , X 2 can react with X 1 and/or X 3 , X 3 can react with X 1 and/or X 2 and so forth.
  • a trivalent core will be directly or indirectly bonded to three functional groups, a tetravalent core will be directly or indirectly bonded to four functional groups, etc.
  • Each side chain typically has one reactive group.
  • the invention also encompasses self-reactive compounds where the side chains contain more than one reactive group.
  • the self-reactive compound has the formula (II): [X' - (L ) a - Y' - (L 5 ) b ] c R 1
  • the compound is essentially non-reactive in an initial environment but is rendered reactive upon exposure to a modification in the initial environment that provides a modified environment such that a plurality of the self-reactive compounds inter-react in the modified environment to form a three-dimensional matrix.
  • R is a hydrophilic polymer.
  • X' is a nucleophilic group and Y * is an electrophilic group.
  • the following self-reactive compound is one example of a compound of formula (II):
  • R has the formula:
  • the self-reactive compounds of the invention are readily synthesized by techniques that are well known in the art. An exemplary synthesis is set forth below:
  • the reactive groups are selected so that the compound is essentially non-reactive in an initial environment.
  • the compound Upon exposure to a specific modification in the initial environment, providing a modified environment, the compound is rendered reactive and a plurality of self-reactive compounds are then able to inter-react in the modified environment to form a three-dimensional matrix.
  • modification in the initial environment include the addition of an aqueous medium, a change in pH, exposure to ultraviolet radiation, a change in temperature, or contact with a redox initiator.
  • the core and reactive groups can also be selected so as to provide a compound that has one of more of the following features: are biocompatible, are non-immunogenic, and do not leave any toxic, inflammatory or immunogenic reaction products at the site of administration.
  • the core and reactive groups can also be selected so as to provide a resulting matrix that has one or more of these features.
  • substantially immediately or immediately upon exposure to the modified environment the self-reactive compounds inter-react form a three-dimensional matrix.
  • the term "substantially immediately” is intended to mean within less than five minutes, preferably within less than two minutes, and the term “immediately” is intended to mean within less than one minute, preferably within less than 30 seconds.
  • the self-reactive compound and resulting matrix are not subject to enzymatic cleavage by matrix metalloproteinases such as collagenase, and are therefore not readily degradable in vivo.
  • the self-reactive compound may be readily tailored, in terms of the selection and quantity of each component, to enhance certain properties, e.g., compression strength, swellability, tack, hydrophilicity, optical clarity, and the like.
  • R is a hydrophilic polymer.
  • X is a nucleophilic group
  • Y is an electrophilic group
  • Z is either an electrophilic or a nucleophilic group. Additional embodiments are detailed below.
  • a higher degree of inter-reaction e.g., crosslinking
  • n be an integer from 2-12.
  • the compounds may be the same or different.
  • the self-reactive compound Prior to use, the self-reactive compound is stored in an initial environment that insures that the compound remain essentially non-reactive until use. Upon modification of this environment, the compound is rendered reactive and a plurality of compounds will then inter-react to form the desired matrix.
  • the initial environment, as well as the modified environment, is thus determined by the nature of the reactive groups involved.
  • the number of reactive groups can be the same or different. However, in one embodiment of the invention, the number of reactive groups is approximately equal.
  • the term "approximately” refers to a 2:1 to 1 :2 ratio of moles of one reactive group to moles of a different reactive groups. A 1 :1 :1 molar ratio of reactive groups is generally preferred.
  • the concentration of the self-reactive compounds in the modified environment when liquid in nature, will be in the range of about 1 to 50 wt%, generally about 2 to 40 wt%.
  • the preferred concentration of the compound in the liquid will depend on a number of factors, including the type of compound (i.e., type of molecular core and reactive groups), its molecular weight, and the end use of the resulting three-dimensional matrix. For example, use of higher concentrations of the compounds, or using highly functionalized compounds, will result in the formation of a more tightly crosslinked network, producing a stiffer, more robust gel.
  • compositions intended for use in tissue augmentation will generally employ concentrations of self-reactive compounds that fall toward the higher end of the preferred concentration range.
  • Compositions intended for use as bioadhesives or in adhesion prevention do not need to be as firm and may therefore contain lower concentrations of the self-reactive compounds.
  • the reactive groups are electrophilic and nucleophilic groups, which undergo a nucleophilic substitution reaction, a nucleophilic addition reaction, or both.
  • electrophilic refers to a reactive group that is susceptible to nucleophilic attack, i.e., susceptible to reaction with an incoming nucleophilic group.
  • Electrophilic groups herein are positively charged or electron-deficient, typically electron- deficient.
  • nucleophilic refers to a reactive group that is electron rich, has an unshared pair of electrons acting as a reactive site, and reacts with a positively charged or electron-deficient site.
  • the modification in the initial environment comprises the addition of an aqueous medium and/or a change in pH.
  • X1 also referred to herein as
  • X can be a nucleophilic group and X2 (also referred to herein as Y) can be an electrophilic group or vice versa, and X3 (also referred to herein as Z) can be either an electrophilic or a nucleophilic group.
  • X may be virtually any nucleophilic group, so long as reaction can occur with the electrophilic group Y and also with Z, when Z is electrophilic (Z E L).
  • Y may be virtually any electrophilic group, so long as reaction can take place with X and also with Z when Z is nucleophilic (ZNU)-
  • ZNU nucleophilic
  • the only limitation is a practical one, in that reaction between X and Y, and X and ZEL, or Y and ZNU should be fairly rapid and take place automatically upon admixture with an aqueous medium, without need for heat or potentially toxic or non-biodegradable reaction catalysts or other chemical reagents. It is also preferred although not essential that reaction occur without need for ultraviolet or other radiation.
  • the reactions between X and Y, and between either X and Z E L or Y and ZNU are complete in under 60 minutes, preferably under 30 minutes.
  • nucleophilic groups suitable as X or Fn N u include, but are not limited to: -NH 2 , -NHR 1 , -N(R 1 ) 2 , -SH, -OH, -COOH, -C 6 H 4 -OH, -H, -PH 2 , -PHR 1 , -P(R 1 ) 2> -NH-NH 2 , -CO-NH-NH 2 , -C 5 H 4 N, etc. wherein R 1 is a hydrocarbyl group and each R1 may be the same or different.
  • R 1 is typically alkyl or monocyclic aryl, preferably alkyl, and most preferably lower alkyl.
  • Organometallic moieties are also useful nucleophilic groups for the purposes of the invention, particularly those that act as carbanion donors.
  • organometallic moieties include: Grignard functionalities -R 2 MgHal wherein R 2 is a carbon atom (substituted or unsubstituted), and Hal is halo, typically bromo, iodo or chloro, preferably bromo; and lithium-containing functionalities, typically alkyllithium groups; sodium-containing functionalities.
  • nucleophilic groups must be activated with a base so as to be capable of reaction with an electrophilic group.
  • the compound when there are nucleophilic sulfhydryl and hydroxyl groups in the self-reactive compound, the compound must be admixed with an aqueous base in order to remove a proton and provide an -S " or -O " species to enable reaction with the electrophilic group.
  • a non- nucleophilic base is preferred.
  • the base may be present as a component of a buffer solution. Suitable bases and corresponding crosslinking reactions are described herein.
  • electrophilic groups provided on the self-reactive compound must be made so that reaction is possible with the specific nucleophilic groups.
  • the Y and any Z E ⁇ _ groups are selected so as to react with amino groups.
  • the corresponding electrophilic groups are sulfhydryl-reactive groups, and the like.
  • the amine-reactive groups contain an electrophilically reactive carbonyl group susceptible to nucleophilic attack by a primary or secondary amine, for example the carboxylic acid esters and aldehydes noted above, as well as carboxyl groups (-COOH). Since a carboxylic acid group per se is not susceptible to reaction with a nucleophilic amine, components containing carboxylic acid groups must be activated so as to be amine-reactive. Activation may be accomplished in a variety of ways, but often involves reaction with a suitable hydroxyl-containing compound in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or dicyclohexylurea (DHU).
  • DCC dicyclohexylcarbodiimide
  • DHU dicyclohexylurea
  • a carboxylic acid can be reacted with an alkoxy-substituted N-hydroxy- succinimide or N-hydroxysulfosuccinimide in the presence of DCC to form reactive electrophilic groups, the N-hydroxysuccinimide ester and the N- hydroxysulfosuccinimide ester, respectively.
  • Carboxylic acids may also be activated by reaction with an acyl halide such as an acyl chloride (e.g., acetyl chloride), to provide a reactive anhydride group.
  • a carboxylic acid may be converted to an acid chloride group using, e.g., thionyl chloride or an acyl chloride capable of an exchange reaction.
  • the amine-reactive groups are selected from succinimidyl ester (-0(CO)-N(COCH )2), sulfosuccinimidyl ester (-0(CO)-N(COCH 2 ) 2 -S(0) 2 OH), maleimido (-N(COCH) 2 ), epoxy, isocyanato, thioisocyanato, and ethenesulfonyl.
  • the electrophilic groups present on Y and Z E ⁇ _ are groups that react with a sulfhydryl moiety.
  • Such reactive groups include those that form thioester linkages upon reaction with a sulfhydryl group, such as those described in WO 00/62827 to Wallace et al.
  • sulfhydryl reactive groups include, but are not limited to: mixed anhydrides; ester derivatives of phosphorus; ester derivatives of p-nitrophenol, p-nitrothiophenol and pentafluorophenol; esters of substituted hydroxylamines, including N-hydroxyphthalimide esters, N-hydroxysuccinimide esters, N- hydroxysulfosuccinimide esters, and N-hydroxyglutarimide esters; esters of 1- hydroxybenzotriazole; 3-hydroxy-3,4-dihydro-benzotriazin-4-one; 3-hydroxy- 3,4-dihydro-quinazoline-4-one; carbonylimidazole derivatives; acid chlorides; ketenes; and isocyanates.
  • auxiliary reagents can also be used to facilitate bond formation, e.g., 1 -ethyl-3-[3- dimethylaminopropyl]carbodiimide can be used to facilitate coupling of sulfhydryl groups to carboxyl-containing groups.
  • various other sulfhydryl reactive functionalities can be utilized that form other types of linkages. For example, compounds that contain methyl imidate derivatives form imido-thioester linkages with sulfhydryl groups.
  • sulfhydryl reactive groups can be employed that form disulfide bonds with sulfhydryl groups; such groups generally have the structure -S-S-Ar where Ar is a substituted or unsubstituted nitrogen-containing heteroaromatic moiety or a non-heterocyclic aromatic group substituted with an electron- withdrawing moiety, such that Ar may be, for example, 4-pyridinyl, o- nitrophenyl, m-nitrophenyl, p-nitrophenyl, 2,4-dinitrophenyl, 2-nitro-4-benzoic acid, 2-nitro-4-pyridinyl, etc.
  • auxiliary reagents i.e., mild oxidizing agents such as hydrogen peroxide
  • sulfhydryl reactive groups forms thioether bonds with sulfhydryl groups.
  • groups include, inter alia, maleimido, substituted maleimido, haloalkyl, epoxy, imino, and aziridino, as well as olefins (including conjugated olefins) such as ethenesulfonyl, etheneimino, acrylate, methacrylate, and ⁇ , ⁇ -unsaturated aldehydes and ketones.
  • the electrophilic functional groups on the remaining component(s) must react with hydroxyl groups.
  • the hydroxyl group may be activated as described above with respect to carboxylic acid groups, or it may react directly in the presence of base with a sufficiently reactive electrophilic group such as an epoxide group, an aziridine group, an acyl halide, an anhydride, and so forth.
  • X is an organometallic nucleophilic group such as a Grignard functionality or an alkyllithium group
  • suitable electrophilic functional groups for reaction therewith are those containing carbonyl groups, including, by way of example, ketones and aldehydes.
  • nucleophilic or electrophilic groups can react as nucleophilic or as electrophilic groups, depending on the selected reaction partner and/or the reaction conditions.
  • a carboxylic acid group can act as a nucleophilic group in the presence of a fairly strong base, but generally acts as an electrophilic group allowing nucleophilic attack at the carbonyl carbon and concomitant replacement of the hydroxyl group with the incoming nucleophilic group.
  • the initial environment typically can be dry and sterile. Since electrophilic groups react with water, storage in sterile, dry form will prevent hydrolysis.
  • the dry synthetic polymer may be compression molded into a thin sheet or membrane, which can then be sterilized using gamma or e- beam irradiation. The resulting dry membrane or sheet can be cut to the desired size or chopped into smaller size particulates.
  • the modification of a dry initial environment will typically comprise the addition of an aqueous medium.
  • the initial environment can be an aqueous medium such as in a low pH buffer, i.e., having a pH less than about 6.0, in which both electrophilic and nucleophilic groups are non-reactive.
  • aqueous buffer solutions such as monobasic sodium phosphate/dibasic sodium phosphate, sodium carbonate/sodium bicarbonate, glutamate or acetate, at a concentration of 0.5 to 300 mM.
  • Modification of an initial low pH aqueous environment will typically comprise increasing the pH to at least pH 7.0, more preferably increasing the pH to at least pH 9.5.
  • the modification of a dry initial environment comprises dissolving the self-reactive compound in a first buffer solution having a pH within the range of about 1.0 to 5.5 to form a homogeneous solution, and (ii) adding a second buffer solution having a pH within the range of about 6.0 to 11.0 to the homogeneous solution.
  • the buffer solutions are aqueous and can be any pharmaceutically acceptable basic or acid composition.
  • the term "buffer" is used in a general sense to refer to an acidic or basic aqueous solution, where the solution may or may not be functioning to provide a buffering effect (i.e., resistance to change in pH upon addition of acid or base) in the compositions of the present invention.
  • the self-reactive compound can be in the form of a homogeneous dry powder.
  • This powder is then combined with a buffer solution having a pH within the range of about 1.0 to 5.5 to form a homogeneous acidic aqueous solution, and this solution is then combined with a buffer solution having a pH within the range of about 6.0 to 11.0 to form a reactive solution.
  • 0.375 grams of the dry powder can be combined with 0.75 grams of the acid buffer to provide, after mixing, a homogeneous solution, where this solution is combined with 1.1 grams of the basic buffer to provide a reactive mixture that substantially immediately forms a three-dimensional matrix.
  • Acidic buffer solutions having a pH within the range of about 1.0 to 5.5 include by way of illustration and not limitation, solutions of: citric acid, hydrochloric acid, phosphoric acid, sulfuric acid, AMPSO (3-[(1 ,1-dimethyl-2- hydroxyethyl)amino]2-hydroxy-propane-sulfonic acid), acetic acid, lactic acid, and combinations thereof.
  • the acidic buffer solution is a solution of citric acid, hydrochloric acid, phosphoric acid, sulfuric acid, and combinations thereof.
  • the acidic buffer preferably has a pH such that it retards the reactivity of the nucleophilic groups on the core.
  • the acidic buffer is an acidic solution that, when contacted with nucleophilic groups, renders those nucleophilic groups relatively non-nucleophilic.
  • An exemplary acidic buffer is a solution of hydrochloric acid, having a concentration of about 6.3 mM and a pH in the range of 2.1 to 2.3. This buffer may be prepared by combining concentrated hydrochloric acid with water, i.e., by diluting concentrated hydrochloric acid with water.
  • this buffer A may also be conveniently prepared by diluting 1.23 grams of concentrated hydrochloric acid to a volume of 2 liters, or diluting 1.84 grams of concentrated hydrochloric acid to a volume to 3 liters, or diluting 2.45 grams of concentrated hydrochloric acid to a volume of 4 liters, or diluting 3.07 grams concentrated hydrochloric acid to a volume of 5 liters, or diluting 3.68 grams of concentrated hydrochloric acid to a volume to 6 liters.
  • the concentrated acid is preferably added to water.
  • Basic buffer solutions having a pH within the range of about 6.0 to 11.0 include by way of illustration and not limitation, solutions of: glutamate, acetate, carbonate and carbonate salts (e.g., sodium carbonate, sodium carbonate monohydrate and sodium bicarbonate), borate, phosphate and phosphate salts (e.g., monobasic sodium phosphate monohydrate and dibasic sodium phosphate), and combinations thereof.
  • the basic buffer solution is a solution of carbonate salts, phosphate salts, and combinations thereof.
  • the basic buffer is an aqueous solution that neutralizes the effect of the acidic buffer, when it is added to the homogeneous solution of the compound and first buffer, so that the nucleophilic groups on the core regain their nucleophilic character (that has been masked by the action of the acidic buffer), thus allowing the nucleophilic groups to inter-react with the electrophilic groups on the core.
  • An exemplary basic buffer is an aqueous solution of carbonate and phosphate salts. This buffer may be prepared by combining a base solution with a salt solution. The salt solution may be prepared by combining 34.7 g of monobasic sodium phosphate monohydrate, 49.3 g of sodium carbonate monohydrate, and sufficient water to provide a solution volume of 2 liter.
  • a 6 liter solution may be prepared by combining 104.0 g of monobasic sodium phosphate monohydrate, 147.94 g of sodium carbonate monohydrate, and sufficient water to provide 6 liter of the salt solution.
  • the basic buffer may be prepared by combining 7.2 g of sodium hydroxide with 180.0 g of water.
  • the basic buffer is typically prepared by adding the base solution as needed to the salt solution, ultimately to provide a mixture having the desired pH, e.g., a pH of 9.65 to 9.75.
  • the basic species present in the basic buffer should be sufficiently basic to neutralize the acidity provided by the acidic buffer, but should not be so nucleophilic itself that it will react substantially with the electrophilic groups on the core.
  • a three-dimensional matrix of the present invention may combine an admixture of the self-reactive compound with a first, acidic, buffer (e.g., an acid solution, e.g., a dilute hydrochloric acid solution) to form a homogeneous solution.
  • a first, acidic, buffer e.g., an acid solution, e.g., a dilute hydrochloric acid solution
  • This homogeneous solution is mixed with a second, basic, buffer (e.g., a basic solution, e.g., an aqueous solution containing phosphate and carbonate salts) whereupon the reactive groups on the core of the self-reactive compound substantially immediately inter-react with one another to form a three- dimensional matrix.
  • the reactive groups are vinyl groups such as styrene derivatives, which undergo a radical polymerization upon initiation with a redox initiator.
  • redox refers to a reactive group that is susceptible to oxidation-reduction activation.
  • vinyl refers to a reactive group that is activated by a redox initiator, and forms a radical upon reaction.
  • X, Y and Z can be the same or different vinyl groups, for example, methacrylic groups.
  • the initial environment typically will be an aqueous environment. The modification of the initial environment involves the addition of a redox initiator.
  • the reactive groups undergo an oxidative coupling reaction.
  • X, Y and Z can be a halo group such as chloro, with an adjacent electron-withdrawing group on the halogen- bearing carbon (e.g., on the "L" linking group).
  • exemplary electron-withdrawing groups include nitro, aryl, and so forth.
  • the modification in the initial environment comprises a change in pH.
  • a base such as KOH
  • the self-reactive compounds then undergo a de-hydro, chloro coupling reaction, forming a double bond between the carbon atoms, as illustrated below:
  • the initial environment typically can be can be dry and sterile, or a non-basic medium.
  • the modification of the initial environment will typically comprise the addition of a base.
  • the reactive groups are photoinitiated groups.
  • the modification in the initial environment comprises exposure to ultraviolet radiation.
  • X can be an azide (-N 3 ) group and Y can be an alkyl group such as -CH(CH 3 ) 2 or vice versa. Exposure to ultraviolet radiation will then form a bond between the groups to provide for the following linkage: -NH-C(CH 3 ) 2 -CH 2 -.
  • X can be a benzophenone (-(C 6 H 4 )-C(0)-(C 6 H 5 )) group and Y can be an alkyl group such as -CH(CH 3 ) 2 or vice versa. Exposure to ultraviolet radiation will then form a bond between the groups to provide for the following linkage:
  • the initial environment typically will be in an ultraviolet radiation- shielded environment. This can be for example, storage within a container that is impermeable to ultraviolet radiation.
  • the modification of the initial environment will typically comprise exposure to ultraviolet radiation.
  • the reactive groups are temperature-sensitive groups, which undergo a thermochemical reaction.
  • the modification in the initial environment thus comprises a change in temperature.
  • the term "temperature-sensitive” refers to a reactive group that is chemically inert at one temperature or temperature range and reactive at a different temperature or temperature range.
  • X, Y, and Z are the same or different vinyl groups.
  • the initial environment typically will be within the range of about 10 to 30°C.
  • the modification of the initial environment will typically comprise changing the temperature to within the range of about 20 to 40°C. F.
  • Linking Groups The reactive groups may be directly attached to the core, or they may be indirectly attached through a linking group, with longer linking groups also termed "chain extenders.”
  • chain extenders In the formula (I) shown above, the optional linker groups are represented by L 1 , L 2 , and L 3 , wherein the linking groups are present when p, q and r are equal to 1.
  • Suitable linking groups are well known in the art. See, for example, WO 97/22371 to Rhee et al. Linking groups are useful to avoid steric hindrance problems that can sometimes associated with the formation of direct linkages between molecules. Linking groups may additionally be used to link several self-reactive compounds together to make larger molecules.
  • a linking group can be used to alter the degradative properties of the compositions after administration and resultant gel formation.
  • linking groups can be used to promote hydrolysis, to discourage hydrolysis, or to provide a site for enzymatic degradation.
  • Examples of linking groups that provide hydrolyzable sites include, inter alia: ester linkages; anhydride linkages, such as those obtained by incorporation of glutarate and succinate; ortho ester linkages; ortho carbonate linkages such as trimethylene carbonate; amide linkages; phosphoester linkages; ⁇ -hydroxy acid linkages, such as those obtained by incorporation of lactic acid and glycolic acid; lactone-based linkages, such as those obtained by incorporation of caprolactone, valerolactone, ⁇ -butyrolactone and p-dioxanone; and amide linkages such as in a dimeric, oligomeric, or poly(amino acid) segment.
  • non-degradable linking groups include succinimide, propionic acid and carboxymethylate linkages. See, for example, WO 99/07417 to Coury et al.
  • enzymatically degradable linkages include Leu- Gly-Pro-Ala, which is degraded by collagenase; and Gly-Pro-Lys, which is degraded by plasmin.
  • Linking groups can also be included to enhance or suppress the reactivity of the various reactive groups. For example, electron-withdrawing groups within one or two carbons of a sulfhydryl group would be expected to diminish its effectiveness in coupling, due to a lowering of nucleophilicity. Carbon-carbon double bonds and carbonyl groups will also have such an effect.
  • x is generally in the range of 1 to about 10;
  • R is generally hydrocarbyl, typically alkyl or aryl, preferably alkyl, and most preferably lower alkyl; and
  • R 3 is hydrocarbylene, heteroatom-containing hydrocarbylene, substituted hydrocarbylene, or substituted heteroatom- containing hydrocarbylene) typically alkylene or arylene (again, optionally substituted and/or containing a heteroatom), preferably lower alkylene (e.g., methylene, ethylene, n-propylene, n-butylene, etc.), phenylene, or amidoalkylene (e.g., -(CO)-NH-CH 2 ).
  • lower alkylene e.g., methylene, ethylene, n-propylene, n-butylene, etc.
  • phenylene or amidoalkylene (e.g., -(CO)-NH-CH 2 ).
  • linking groups are as follows. If a higher molecular weight self-reactive compound is to be used, it will preferably have biodegradable linkages as described above, so that fragments larger than 20,000 mol. wt. are not generated during resorption in the body. In addition, to promote water miscibility and/or solubility, it may be desired to add sufficient electric charge or hydrophilicity. Hydrophilic groups can be easily introduced using known chemical synthesis, so long as they do not give rise to unwanted swelling or an undesirable decrease in compressive strength. In particular, polyalkoxy segments may weaken gel strength.
  • the Core The "core" of each self-reactive compound is comprised of the molecular structure to which the reactive groups are bound.
  • the molecular core can a polymer, which includes synthetic polymers and naturally occurring polymers.
  • the core is a polymer containing repeating monomer units.
  • the polymers can be hydrophilic, hydrophobic, or amphiphilic.
  • the molecular core can also be a low molecular weight components such as a C 2-14 hydrocarbyl or a heteroatom-containing C 2 - 14 hydrocarbyl.
  • the heteroatom-containing C- 2 - 14 hydrocarbyl can have 1 or 2 heteroatoms selected from N, O and S.
  • the self-reactive compound comprises a molecular core of a synthetic hydrophilic polymer.
  • hydrophilic polymer refers to a polymer having an average molecular weight and composition that naturally renders, or is selected to render the polymer as a whole "hydrophilic.” Preferred polymers are highly pure or are purified to a highly pure state such that the polymer is or is treated to become pharmaceutically pure. Most hydrophilic polymers can be rendered water soluble by incorporating a sufficient number of oxygen (or less frequently nitrogen) atoms available for forming hydrogen bonds in aqueous solutions.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Immunology (AREA)
  • Transplantation (AREA)
  • Molecular Biology (AREA)
  • Radiology & Medical Imaging (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Dermatology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Surgery (AREA)
  • Zoology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Botany (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Rheumatology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP04811760A 2003-11-20 2004-11-22 Electrical devices and anti-scarring agents Withdrawn EP1687043A2 (en)

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
US52390803P 2003-11-20 2003-11-20
US52402303P 2003-11-20 2003-11-20
US52522603P 2003-11-24 2003-11-24
US52654103P 2003-12-03 2003-12-03
US57847104P 2004-06-09 2004-06-09
US58686104P 2004-07-09 2004-07-09
US10/986,230 US20050148512A1 (en) 2003-11-10 2004-11-10 Medical implants and fibrosis-inducing agents
US10/986,231 US20050181977A1 (en) 2003-11-10 2004-11-10 Medical implants and anti-scarring agents
PCT/US2004/039099 WO2005051451A2 (en) 2003-11-20 2004-11-22 Electrical devices and anti-scarring agents

Publications (1)

Publication Number Publication Date
EP1687043A2 true EP1687043A2 (en) 2006-08-09

Family

ID=34637512

Family Applications (3)

Application Number Title Priority Date Filing Date
EP04817879A Withdrawn EP1685085A2 (en) 2003-11-20 2004-11-22 Implantable sensors and implantable pumps and anti-scarring agents
EP04811760A Withdrawn EP1687043A2 (en) 2003-11-20 2004-11-22 Electrical devices and anti-scarring agents
EP04812062A Withdrawn EP1687041A2 (en) 2003-11-20 2004-11-22 Soft tissue implants and anti-scarring agents

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP04817879A Withdrawn EP1685085A2 (en) 2003-11-20 2004-11-22 Implantable sensors and implantable pumps and anti-scarring agents

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP04812062A Withdrawn EP1687041A2 (en) 2003-11-20 2004-11-22 Soft tissue implants and anti-scarring agents

Country Status (6)

Country Link
US (35) US20050158356A1 (US20050142162A1-20050630-C00074.png)
EP (3) EP1685085A2 (US20050142162A1-20050630-C00074.png)
JP (3) JP2007514472A (US20050142162A1-20050630-C00074.png)
AU (3) AU2004293030A1 (US20050142162A1-20050630-C00074.png)
CA (3) CA2536188A1 (US20050142162A1-20050630-C00074.png)
WO (6) WO2006055008A2 (US20050142162A1-20050630-C00074.png)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10252039B2 (en) 2009-12-24 2019-04-09 Rani Therapeutics, Llc Therapeutic agent preparations into a lumen of the intestinal tract using a swallowable drug delivery device
US10307579B2 (en) 2010-12-23 2019-06-04 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10335463B2 (en) 2010-12-23 2019-07-02 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10350163B2 (en) 2010-12-23 2019-07-16 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10478396B2 (en) 2010-12-23 2019-11-19 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10487145B2 (en) 2010-12-23 2019-11-26 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10548850B2 (en) 2010-12-23 2020-02-04 Rani Therapeutics, Llc Therapeutic composition comprising insulin prepared for delivery into an intestinal tract
US10632251B2 (en) 2010-12-23 2020-04-28 Rani Therapeutics, Llc Device, system and methods for the oral delivery of therapeutic compounds
US10639272B2 (en) 2010-12-23 2020-05-05 Rani Therapeutics, Llc Methods for delivering etanercept preparations into a lumen of the intestinal tract using a swallowable drug delivery device
US10752681B2 (en) 2010-12-23 2020-08-25 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10864254B2 (en) 2010-12-23 2020-12-15 Rani Therapeutics, Llc Method of delivering gonadotropin releasing hormone or an analogue thereof into a lumen of the intestinal tract using a swallowable drug delivery device
US10874840B2 (en) 2010-12-23 2020-12-29 Rani Therapeutics, Llc Preparation comprising exanatide for delivery into a lumen of the intestinal tract
US10953077B2 (en) 2010-12-23 2021-03-23 Rani Therapeutics, Llc Method of delivering a somatostatin compound into a lumen of the intestinal tract using a swallowable drug delivery device
US10967050B2 (en) 2010-12-23 2021-04-06 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US11439817B2 (en) 2009-08-03 2022-09-13 Incube Labs, Llc Swallowable capsule and method for stimulating incretin production within the intestinal tract

Families Citing this family (602)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8527026B2 (en) 1997-03-04 2013-09-03 Dexcom, Inc. Device and method for determining analyte levels
US6001067A (en) 1997-03-04 1999-12-14 Shults; Mark C. Device and method for determining analyte levels
US5931855A (en) 1997-05-21 1999-08-03 Frank Hoffman Surgical methods using one-way suture
US8288745B2 (en) 1997-10-10 2012-10-16 Senorx, Inc. Method of utilizing an implant for targeting external beam radiation
US7637948B2 (en) * 1997-10-10 2009-12-29 Senorx, Inc. Tissue marking implant
US8668737B2 (en) 1997-10-10 2014-03-11 Senorx, Inc. Tissue marking implant
US6036924A (en) 1997-12-04 2000-03-14 Hewlett-Packard Company Cassette of lancet cartridges for sampling blood
US6391005B1 (en) 1998-03-30 2002-05-21 Agilent Technologies, Inc. Apparatus and method for penetration with shaft having a sensor for sensing penetration depth
US20090216118A1 (en) 2007-07-26 2009-08-27 Senorx, Inc. Polysaccharide markers
US8498693B2 (en) 1999-02-02 2013-07-30 Senorx, Inc. Intracorporeal marker and marker delivery device
US8361082B2 (en) 1999-02-02 2013-01-29 Senorx, Inc. Marker delivery device with releasable plug
US7983734B2 (en) 2003-05-23 2011-07-19 Senorx, Inc. Fibrous marker and intracorporeal delivery thereof
US9820824B2 (en) 1999-02-02 2017-11-21 Senorx, Inc. Deployment of polysaccharide markers for treating a site within a patent
US7651505B2 (en) 2002-06-17 2010-01-26 Senorx, Inc. Plugged tip delivery for marker placement
US6725083B1 (en) 1999-02-02 2004-04-20 Senorx, Inc. Tissue site markers for in VIVO imaging
US6862470B2 (en) 1999-02-02 2005-03-01 Senorx, Inc. Cavity-filling biopsy site markers
US8285393B2 (en) * 1999-04-16 2012-10-09 Laufer Michael D Device for shaping infarcted heart tissue and method of using the device
US6575991B1 (en) 1999-06-17 2003-06-10 Inrad, Inc. Apparatus for the percutaneous marking of a lesion
US8914114B2 (en) 2000-05-23 2014-12-16 The Feinstein Institute For Medical Research Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation
US7840271B2 (en) 2000-09-27 2010-11-23 Cvrx, Inc. Stimulus regimens for cardiovascular reflex control
US7499742B2 (en) 2001-09-26 2009-03-03 Cvrx, Inc. Electrode structures and methods for their use in cardiovascular reflex control
US7616997B2 (en) 2000-09-27 2009-11-10 Kieval Robert S Devices and methods for cardiovascular reflex control via coupled electrodes
US8086314B1 (en) 2000-09-27 2011-12-27 Cvrx, Inc. Devices and methods for cardiovascular reflex control
US7623926B2 (en) 2000-09-27 2009-11-24 Cvrx, Inc. Stimulus regimens for cardiovascular reflex control
EP2319449B1 (en) 2000-11-20 2016-03-09 Senorx, Inc. Tissue site markers for in vivo imaging
US8641644B2 (en) 2000-11-21 2014-02-04 Sanofi-Aventis Deutschland Gmbh Blood testing apparatus having a rotatable cartridge with multiple lancing elements and testing means
US7431710B2 (en) 2002-04-08 2008-10-07 Glaukos Corporation Ocular implants with anchors and methods thereof
US7678065B2 (en) * 2001-05-02 2010-03-16 Glaukos Corporation Implant with intraocular pressure sensor for glaucoma treatment
US7981056B2 (en) 2002-04-19 2011-07-19 Pelikan Technologies, Inc. Methods and apparatus for lancet actuation
DE60238119D1 (de) 2001-06-12 2010-12-09 Pelikan Technologies Inc Elektrisches betätigungselement für eine lanzette
US8337419B2 (en) 2002-04-19 2012-12-25 Sanofi-Aventis Deutschland Gmbh Tissue penetration device
AU2002348683A1 (en) 2001-06-12 2002-12-23 Pelikan Technologies, Inc. Method and apparatus for lancet launching device integrated onto a blood-sampling cartridge
JP4209767B2 (ja) 2001-06-12 2009-01-14 ペリカン テクノロジーズ インコーポレイテッド 皮膚の性状の一時的変化に対する適応手段を備えた自動最適化形切開器具
US9795747B2 (en) 2010-06-02 2017-10-24 Sanofi-Aventis Deutschland Gmbh Methods and apparatus for lancet actuation
US9427532B2 (en) 2001-06-12 2016-08-30 Sanofi-Aventis Deutschland Gmbh Tissue penetration device
AU2002312521A1 (en) 2001-06-12 2002-12-23 Pelikan Technologies, Inc. Blood sampling apparatus and method
US7041068B2 (en) 2001-06-12 2006-05-09 Pelikan Technologies, Inc. Sampling module device and method
US9226699B2 (en) 2002-04-19 2016-01-05 Sanofi-Aventis Deutschland Gmbh Body fluid sampling module with a continuous compression tissue interface surface
US7699791B2 (en) 2001-06-12 2010-04-20 Pelikan Technologies, Inc. Method and apparatus for improving success rate of blood yield from a fingerstick
US7056331B2 (en) 2001-06-29 2006-06-06 Quill Medical, Inc. Suture method
US20090187230A1 (en) * 2001-07-23 2009-07-23 Dilorenzo Daniel J Method and apparatus for programming of autonomic neuromodulation for the treatment of obesity
US20030032874A1 (en) 2001-07-27 2003-02-13 Dexcom, Inc. Sensor head for use with implantable devices
US7613491B2 (en) 2002-05-22 2009-11-03 Dexcom, Inc. Silicone based membranes for use in implantable glucose sensors
US7951155B2 (en) 2002-03-15 2011-05-31 Glaukos Corporation Combined treatment for cataract and glaucoma treatment
US8702624B2 (en) 2006-09-29 2014-04-22 Sanofi-Aventis Deutschland Gmbh Analyte measurement device with a single shot actuator
US8784335B2 (en) 2002-04-19 2014-07-22 Sanofi-Aventis Deutschland Gmbh Body fluid sampling device with a capacitive sensor
US7892183B2 (en) 2002-04-19 2011-02-22 Pelikan Technologies, Inc. Method and apparatus for body fluid sampling and analyte sensing
US9795334B2 (en) 2002-04-19 2017-10-24 Sanofi-Aventis Deutschland Gmbh Method and apparatus for penetrating tissue
US7901362B2 (en) 2002-04-19 2011-03-08 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US7717863B2 (en) 2002-04-19 2010-05-18 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US7175642B2 (en) 2002-04-19 2007-02-13 Pelikan Technologies, Inc. Methods and apparatus for lancet actuation
US7674232B2 (en) 2002-04-19 2010-03-09 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US8221334B2 (en) 2002-04-19 2012-07-17 Sanofi-Aventis Deutschland Gmbh Method and apparatus for penetrating tissue
US7291117B2 (en) 2002-04-19 2007-11-06 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US7976476B2 (en) 2002-04-19 2011-07-12 Pelikan Technologies, Inc. Device and method for variable speed lancet
US7297122B2 (en) 2002-04-19 2007-11-20 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US7232451B2 (en) 2002-04-19 2007-06-19 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US8579831B2 (en) 2002-04-19 2013-11-12 Sanofi-Aventis Deutschland Gmbh Method and apparatus for penetrating tissue
US7331931B2 (en) 2002-04-19 2008-02-19 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US7648468B2 (en) 2002-04-19 2010-01-19 Pelikon Technologies, Inc. Method and apparatus for penetrating tissue
US9248267B2 (en) 2002-04-19 2016-02-02 Sanofi-Aventis Deustchland Gmbh Tissue penetration device
US7226461B2 (en) 2002-04-19 2007-06-05 Pelikan Technologies, Inc. Method and apparatus for a multi-use body fluid sampling device with sterility barrier release
US7909778B2 (en) 2002-04-19 2011-03-22 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US7229458B2 (en) 2002-04-19 2007-06-12 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US7547287B2 (en) 2002-04-19 2009-06-16 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US8267870B2 (en) 2002-04-19 2012-09-18 Sanofi-Aventis Deutschland Gmbh Method and apparatus for body fluid sampling with hybrid actuation
US7371247B2 (en) 2002-04-19 2008-05-13 Pelikan Technologies, Inc Method and apparatus for penetrating tissue
US7491178B2 (en) 2002-04-19 2009-02-17 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US9314194B2 (en) 2002-04-19 2016-04-19 Sanofi-Aventis Deutschland Gmbh Tissue penetration device
US20080077192A1 (en) 2002-05-03 2008-03-27 Afferent Corporation System and method for neuro-stimulation
US6773450B2 (en) 2002-08-09 2004-08-10 Quill Medical, Inc. Suture anchor and method
US7135027B2 (en) * 2002-10-04 2006-11-14 Baxter International, Inc. Devices and methods for mixing and extruding medically useful compositions
US20060036158A1 (en) 2003-11-17 2006-02-16 Inrad, Inc. Self-contained, self-piercing, side-expelling marking apparatus
US8574895B2 (en) 2002-12-30 2013-11-05 Sanofi-Aventis Deutschland Gmbh Method and apparatus using optical techniques to measure analyte levels
FR2861734B1 (fr) 2003-04-10 2006-04-14 Corneal Ind Reticulation de polysaccharides de faible et forte masse moleculaire; preparation d'hydrogels monophasiques injectables; polysaccharides et hydrogels obtenus
US7877133B2 (en) 2003-05-23 2011-01-25 Senorx, Inc. Marker or filler forming fluid
US8834864B2 (en) * 2003-06-05 2014-09-16 Baxter International Inc. Methods for repairing and regenerating human dura mater
EP1633235B1 (en) 2003-06-06 2014-05-21 Sanofi-Aventis Deutschland GmbH Apparatus for body fluid sampling and analyte sensing
WO2006001797A1 (en) 2004-06-14 2006-01-05 Pelikan Technologies, Inc. Low pain penetrating
JP4708342B2 (ja) 2003-07-25 2011-06-22 デックスコム・インコーポレーテッド 埋設可能な装置に用いる酸素増大膜システム
US7920906B2 (en) 2005-03-10 2011-04-05 Dexcom, Inc. System and methods for processing analyte sensor data for sensor calibration
US7160316B2 (en) * 2003-09-24 2007-01-09 Dynatherm Medical, Inc. Methods and apparatus for adjusting body core temperature
US8182521B2 (en) 2003-09-24 2012-05-22 Dynatherm Medical Inc. Methods and apparatus for increasing blood circulation
US8282576B2 (en) 2003-09-29 2012-10-09 Sanofi-Aventis Deutschland Gmbh Method and apparatus for an improved sample capture device
WO2005037095A1 (en) 2003-10-14 2005-04-28 Pelikan Technologies, Inc. Method and apparatus for a variable user interface
US8708993B1 (en) * 2003-10-15 2014-04-29 Physician Technologies, Inc. Infusion catheter procedure and system
US20050273002A1 (en) 2004-06-04 2005-12-08 Goosen Ryan L Multi-mode imaging marker
US9247900B2 (en) 2004-07-13 2016-02-02 Dexcom, Inc. Analyte sensor
WO2005061088A1 (en) * 2003-12-22 2005-07-07 Finlay Warren H Powder formation by atmospheric spray-freeze drying
US7822454B1 (en) 2005-01-03 2010-10-26 Pelikan Technologies, Inc. Fluid sampling device with improved analyte detecting member configuration
WO2005065414A2 (en) 2003-12-31 2005-07-21 Pelikan Technologies, Inc. Method and apparatus for improving fluidic flow and sample capture
US8057401B2 (en) * 2005-02-24 2011-11-15 Erich Wolf System for transcutaneous monitoring of intracranial pressure
US7435229B2 (en) 2004-02-25 2008-10-14 Wolf Erich W System for transcutaneous monitoring of intracranial pressure (ICP) using near infrared (NIR) telemetry
US7840263B2 (en) 2004-02-27 2010-11-23 Cardiac Pacemakers, Inc. Method and apparatus for device controlled gene expression
EP1734941A2 (en) 2004-03-25 2006-12-27 The Feinstein Institute for Medical Research Neural tourniquet
US10912712B2 (en) 2004-03-25 2021-02-09 The Feinstein Institutes For Medical Research Treatment of bleeding by non-invasive stimulation
US8277713B2 (en) 2004-05-03 2012-10-02 Dexcom, Inc. Implantable analyte sensor
US8288362B2 (en) 2004-05-07 2012-10-16 S.K. Pharmaceuticals, Inc. Stabilized glycosaminoglycan preparations and related methods
NZ598970A (en) 2004-05-14 2013-07-26 Ethicon Llc Suture device using an enlongated body with barbs and a needle at one end and an anchor to prevent pull-through at the other end
US8828203B2 (en) 2004-05-20 2014-09-09 Sanofi-Aventis Deutschland Gmbh Printable hydrogels for biosensors
US9820684B2 (en) 2004-06-03 2017-11-21 Sanofi-Aventis Deutschland Gmbh Method and apparatus for a fluid sampling device
US8696564B2 (en) * 2004-07-09 2014-04-15 Cardiac Pacemakers, Inc. Implantable sensor with biocompatible coating for controlling or inhibiting tissue growth
US8886272B2 (en) 2004-07-13 2014-11-11 Dexcom, Inc. Analyte sensor
US20060020192A1 (en) 2004-07-13 2006-01-26 Dexcom, Inc. Transcutaneous analyte sensor
US7999806B2 (en) * 2004-07-23 2011-08-16 Panasonic Corporation Three-dimensional shape drawing device and three-dimensional shape drawing method
CA2575988C (en) 2004-08-04 2014-02-18 Brookwood Pharmaceuticals, Inc. Methods for manufacturing delivery devices and devices thereof
WO2006020994A2 (en) * 2004-08-13 2006-02-23 Angiotech International Ag Compositions and methods using hyaluronic acid and hyluronidase inhibitors
US9012506B2 (en) 2004-09-28 2015-04-21 Atrium Medical Corporation Cross-linked fatty acid-based biomaterials
US9000040B2 (en) 2004-09-28 2015-04-07 Atrium Medical Corporation Cross-linked fatty acid-based biomaterials
US9801982B2 (en) 2004-09-28 2017-10-31 Atrium Medical Corporation Implantable barrier device
US8312836B2 (en) 2004-09-28 2012-11-20 Atrium Medical Corporation Method and apparatus for application of a fresh coating on a medical device
US20060067977A1 (en) 2004-09-28 2006-03-30 Atrium Medical Corporation Pre-dried drug delivery coating for use with a stent
US8367099B2 (en) 2004-09-28 2013-02-05 Atrium Medical Corporation Perforated fatty acid films
EP1811935B1 (en) 2004-09-28 2016-03-30 Atrium Medical Corporation Heat cured gel and method of making
US20090088846A1 (en) 2007-04-17 2009-04-02 David Myung Hydrogel arthroplasty device
US7200437B1 (en) * 2004-10-13 2007-04-03 Pacesetter, Inc. Tissue contact for satellite cardiac pacemaker
WO2006051539A2 (en) * 2004-11-12 2006-05-18 Shaul Ozeri A miniature infusion pump for a controlled delivery of medication
US8062658B2 (en) 2004-12-14 2011-11-22 Poly-Med, Inc. Multicomponent bioactive intravaginal ring
US20060134071A1 (en) * 2004-12-20 2006-06-22 Jeffrey Ross Use of extracellular matrix and electrical therapy
US8060219B2 (en) 2004-12-20 2011-11-15 Cardiac Pacemakers, Inc. Epicardial patch including isolated extracellular matrix with pacing electrodes
US8874204B2 (en) 2004-12-20 2014-10-28 Cardiac Pacemakers, Inc. Implantable medical devices comprising isolated extracellular matrix
US7981065B2 (en) * 2004-12-20 2011-07-19 Cardiac Pacemakers, Inc. Lead electrode incorporating extracellular matrix
EP1833559B1 (en) 2004-12-27 2010-11-24 The Feinstein Institute for Medical Research Treating inflammatory disorders by electrical vagus nerve stimulation
US11207518B2 (en) 2004-12-27 2021-12-28 The Feinstein Institutes For Medical Research Treating inflammatory disorders by stimulation of the cholinergic anti-inflammatory pathway
US8652831B2 (en) 2004-12-30 2014-02-18 Sanofi-Aventis Deutschland Gmbh Method and apparatus for analyte measurement test time
US20070156210A1 (en) * 2005-01-14 2007-07-05 Co-Repair, Inc., A California Corporation Method for the treatment of heart tissue
US7455670B2 (en) * 2005-01-14 2008-11-25 Co-Repair, Inc. System and method for the treatment of heart tissue
US20070156209A1 (en) * 2005-01-14 2007-07-05 Co-Repair, Inc. System for the treatment of heart tissue
JP2008537684A (ja) * 2005-01-24 2008-09-25 ニューロシステック コーポレイション 内耳およびその他の組織へ治療薬および／またはその他の薬剤を送達するための装置および方法
US8066759B2 (en) 2005-02-04 2011-11-29 Boston Scientific Scimed, Inc. Resonator for medical device
US8663639B2 (en) 2005-02-09 2014-03-04 Santen Pharmaceutical Co., Ltd. Formulations for treating ocular diseases and conditions
US8637070B2 (en) 2005-02-09 2014-01-28 Santen Pharmaceutical Co., Ltd. Rapamycin formulations and methods of their use
AU2006213822B2 (en) 2005-02-09 2011-05-26 Covidien Lp Synthetic sealants
AU2012202903B2 (en) * 2005-02-18 2014-12-11 Abraxis Bioscience, Inc. Drugs with improved hydrophobicity for incorporation in medical devices
CN101146514B (zh) * 2005-02-18 2013-03-27 阿布拉西斯生物科学公司 用于整合入医疗装置的疏水性改善的药物
WO2006094029A2 (en) * 2005-02-28 2006-09-08 Kosan Biosciences Incoporated Pharmaceutical formulations containing 17-allylamino-17-demethoxygeldanamycin
CA2602525A1 (en) * 2005-03-21 2006-09-28 Macusight, Inc. Drug delivery systems for treatment of diseases or conditions
US8744546B2 (en) 2005-05-05 2014-06-03 Dexcom, Inc. Cellulosic-based resistance domain for an analyte sensor
US10357328B2 (en) 2005-04-20 2019-07-23 Bard Peripheral Vascular, Inc. and Bard Shannon Limited Marking device with retractable cannula
DE102005020102B3 (de) * 2005-04-25 2006-11-30 Universität Potsdam Verfahren und Vorrichtung zur Gewinnung und Analyse von Atemkondensaten
US9198608B2 (en) 2005-04-28 2015-12-01 Proteus Digital Health, Inc. Communication system incorporated in a container
US20060247623A1 (en) * 2005-04-29 2006-11-02 Sdgi Holdings, Inc. Local delivery of an active agent from an orthopedic implant
US20100100124A1 (en) * 2005-05-05 2010-04-22 Tyco Healthcare Group Lp Bioabsorbable surgical composition
US8044234B2 (en) * 2005-05-05 2011-10-25 Tyco Healthcare Group Lp Bioabsorbable surgical composition
US7438411B2 (en) * 2005-05-07 2008-10-21 Nanospectra Biosciences, Inc. Plasmon resonant based eye protection
US7736320B2 (en) * 2005-05-25 2010-06-15 Sierra Medical Technology, Inc. Self-condensing pH sensor and catheter apparatus
US7949412B1 (en) 2005-06-02 2011-05-24 Advanced Bionics, Llc Coated electrode array having uncoated electrode contacts
DE102005031575A1 (de) * 2005-07-06 2007-01-11 Bayer Healthcare Ag Verwendung von Aktivatoren der löslichen Guanylatzyklase zur Förderung der Wundheilung
US9119899B2 (en) * 2006-01-18 2015-09-01 Cormatrix Cardiovascular, Inc. Method and system for treatment of cardiovascular disorders
US7279664B2 (en) 2005-07-26 2007-10-09 Boston Scientific Scimed, Inc. Resonator for medical device
US7304277B2 (en) 2005-08-23 2007-12-04 Boston Scientific Scimed, Inc Resonator with adjustable capacitor for medical device
US7524282B2 (en) 2005-08-29 2009-04-28 Boston Scientific Scimed, Inc. Cardiac sleeve apparatus, system and method of use
RU2451510C2 (ru) 2005-08-31 2012-05-27 АБРАКСИС БАЙОСАЙЕНС, ЭлЭлСи Композиции и способы получения слаборастворимых в воде лекарственных средств с увеличенной стабильностью
BRPI0615292A8 (pt) 2005-08-31 2018-03-06 Abraxis Bioscience Llc composições e métodos para preparação de fármacos de má solubilidade em água com estabilidade aumentada
US20070051531A1 (en) * 2005-09-08 2007-03-08 Harshad Borgaonkar Drug eluting coatings for a medical lead and method therefor
US20070112414A1 (en) * 2005-09-08 2007-05-17 Conor Medsystems, Inc. System and method for local delivery of antithrombotics
US9278161B2 (en) 2005-09-28 2016-03-08 Atrium Medical Corporation Tissue-separating fatty acid adhesion barrier
US9427423B2 (en) 2009-03-10 2016-08-30 Atrium Medical Corporation Fatty-acid based particles
US8574627B2 (en) 2006-11-06 2013-11-05 Atrium Medical Corporation Coated surgical mesh
JP4710518B2 (ja) * 2005-09-28 2011-06-29 株式会社日立製作所 計算機システムとそのブート制御方法
WO2007041596A2 (en) * 2005-10-03 2007-04-12 The General Hospital Corporation Compositions and methods for the treatment of cancer
WO2007041584A2 (en) * 2005-10-03 2007-04-12 Combinatorx, Incorporated Implantable sensors, implantable pumps, and anti-scarring drug combinations
WO2007041677A2 (en) * 2005-10-03 2007-04-12 Combinatorx, Incorporated Soft tissue implants and drug combination compositions, and use thereof
CA2562580C (en) 2005-10-07 2014-04-29 Inrad, Inc. Drug-eluting tissue marker
WO2007047556A2 (en) * 2005-10-14 2007-04-26 Microchips, Inc. Passive wear-indicating sensor for implantable prosthetic device
US8038885B2 (en) * 2005-10-14 2011-10-18 The Regents Of The University Of California Formation and encapsulation of molecular bilayer and monolayer membranes
US20070086958A1 (en) * 2005-10-14 2007-04-19 Medafor, Incorporated Formation of medically useful gels comprising microporous particles and methods of use
US9233846B2 (en) * 2005-10-14 2016-01-12 The Regents Of The University Of California Formation and encapsulation of molecular bilayer and monolayer membranes
AU2006304590A1 (en) 2005-10-15 2007-04-26 Atrium Medical Corporation Hydrophobic cross-linked gels for bioabsorbable drug carrier coatings
US8192731B2 (en) * 2005-10-25 2012-06-05 Loctite (R&D) Limited Thickened cyanoacrylate compositions
US7423496B2 (en) 2005-11-09 2008-09-09 Boston Scientific Scimed, Inc. Resonator with adjustable capacitance for medical device
JP2007135965A (ja) * 2005-11-21 2007-06-07 Tohoku Univ 体内留置多機能ステントおよびその製造方法
CA2628580C (en) * 2005-12-06 2014-07-08 Tyco Healthcare Group Lp Bioabsorbable compounds and compositions containing them
EP1968617A4 (en) * 2005-12-06 2012-05-02 Tyco Healthcare BIOCOMPATIBLE TISSUE SEALING ADHESIVES AND AGENTS
CA2628579C (en) 2005-12-06 2014-07-08 Tyco Healthcare Group Lp Carbodiimide crosslinking of functionalized polethylene glycols
CA2628598C (en) 2005-12-06 2015-02-24 Tyco Healthcare Group Lp Bioabsorbable surgical composition
US7947263B2 (en) * 2005-12-06 2011-05-24 Tyco Healthcare Group Lp Biocompatible surgical compositions
US8449714B2 (en) 2005-12-08 2013-05-28 Covidien Lp Biocompatible surgical compositions
US8050774B2 (en) 2005-12-22 2011-11-01 Boston Scientific Scimed, Inc. Electrode apparatus, systems and methods
US8353881B2 (en) * 2005-12-28 2013-01-15 Abbott Diabetes Care Inc. Infusion sets for the delivery of a therapeutic substance to a patient
US20080086200A1 (en) * 2006-01-03 2008-04-10 Heartcor Injectable implants for tissue augmentation and restoration
US20070160640A1 (en) * 2006-01-12 2007-07-12 Eun-Hyun Jang Halofuginone delivering vascular medical devices
US20090038701A1 (en) 2006-01-17 2009-02-12 Baxter International Inc. Device, system and method for mixing
EP2213245B1 (en) * 2006-01-17 2012-07-04 Baxter International Inc. Device and method for mixing
WO2007084516A2 (en) * 2006-01-18 2007-07-26 Dexcom, Inc. Membranes for an analyte sensor
CA2632871A1 (en) * 2006-01-30 2007-08-09 Angiotech Pharmaceuticals, Inc. Sutures and fibrosing agents
EP1978930A2 (en) * 2006-01-31 2008-10-15 Angiotech Pharmaceuticals, Inc. Sutures and anti-scarring agents
WO2007090232A1 (en) * 2006-02-06 2007-08-16 University Of Wollongong Self-powered sensing devices
WO2009113972A2 (en) 2006-02-08 2009-09-17 Tyrx Pharma, Inc. Temporarily stiffened mesh prostheses
US8591531B2 (en) * 2006-02-08 2013-11-26 Tyrx, Inc. Mesh pouches for implantable medical devices
US8315700B2 (en) * 2006-02-08 2012-11-20 Tyrx, Inc. Preventing biofilm formation on implantable medical devices
CA2635797C (en) * 2006-02-09 2015-03-31 Macusight, Inc. Stable formulations, and methods of their preparation and use
JP5234967B2 (ja) 2006-02-27 2013-07-10 エドワーズ ライフサイエンシーズ コーポレイション 静脈内電流測定バイオセンサのための流束制限膜
US7981034B2 (en) 2006-02-28 2011-07-19 Abbott Diabetes Care Inc. Smart messages and alerts for an infusion delivery and management system
US20080183282A1 (en) * 2006-03-09 2008-07-31 Saul Yedgar Use of lipid conjugates for the coating of stents and catheters
US8222271B2 (en) 2006-03-23 2012-07-17 Santen Pharmaceutical Co., Ltd. Formulations and methods for vascular permeability-related diseases or conditions
WO2007120381A2 (en) 2006-04-14 2007-10-25 Dexcom, Inc. Analyte sensor
US20080183237A1 (en) * 2006-04-18 2008-07-31 Electrocore, Inc. Methods And Apparatus For Treating Ileus Condition Using Electrical Signals
ES2396088T3 (es) * 2006-04-26 2013-02-19 Eastern Virginia Medical School Sistemas para monitorizar y controlar la presión interna de un ojo o una parte del cuerpo
US8267905B2 (en) * 2006-05-01 2012-09-18 Neurosystec Corporation Apparatus and method for delivery of therapeutic and other types of agents
CN101496042A (zh) 2006-05-02 2009-07-29 普罗秋斯生物医学公司 患者定制的治疗方案
JP5231401B2 (ja) * 2006-05-31 2013-07-10 バクスター・インターナショナル・インコーポレイテッド 脊髄の手術における導かれた細胞内殖及び制御された組織再生の方法
US20070282376A1 (en) 2006-06-06 2007-12-06 Shuros Allan C Method and apparatus for neural stimulation via the lymphatic system
US7894906B2 (en) 2006-06-06 2011-02-22 Cardiac Pacemakers, Inc. Amelioration of chronic pain by endolymphatic stimulation
US7734341B2 (en) 2006-06-06 2010-06-08 Cardiac Pacemakers, Inc. Method and apparatus for gastrointestinal stimulation via the lymphatic system
US7803148B2 (en) 2006-06-09 2010-09-28 Neurosystec Corporation Flow-induced delivery from a drug mass
US20080172073A1 (en) * 2006-06-16 2008-07-17 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Active blood vessel sleeve
US8550344B2 (en) * 2006-06-16 2013-10-08 The Invention Science Fund I, Llc Specialty stents with flow control features or the like
US20090024152A1 (en) * 2007-07-17 2009-01-22 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Custom-fitted blood vessel sleeve
US20080133040A1 (en) * 2006-06-16 2008-06-05 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for specifying a blood vessel sleeve
US8551155B2 (en) * 2006-06-16 2013-10-08 The Invention Science Fund I, Llc Stent customization system and method
US9119582B2 (en) 2006-06-30 2015-09-01 Abbott Diabetes Care, Inc. Integrated analyte sensor and infusion device and methods therefor
US20100152811A1 (en) * 2006-06-30 2010-06-17 Flaherty Christopher J Nerve regeneration system and lead devices associated therewith
US20120046724A1 (en) * 2006-07-13 2012-02-23 Anna Norlin Weissenrieder implantable cardiac stimulation drug releasing electrode
US7794495B2 (en) * 2006-07-17 2010-09-14 Advanced Cardiovascular Systems, Inc. Controlled degradation of stents
US7615064B2 (en) * 2006-07-26 2009-11-10 J.n Tailor Surgical, Inc. Endolumenal gastric ring with suspended impeding member
US20080027541A1 (en) * 2006-07-31 2008-01-31 Gerut Zachary E Method and device for treating breast implant encapsulation
US20080183124A1 (en) * 2006-07-31 2008-07-31 Gerut Zachary E Method and device for treating breast implant encapsulation
US8932216B2 (en) 2006-08-07 2015-01-13 Abbott Diabetes Care Inc. Method and system for providing data management in integrated analyte monitoring and infusion system
US8206296B2 (en) 2006-08-07 2012-06-26 Abbott Diabetes Care Inc. Method and system for providing integrated analyte monitoring and infusion system therapy management
US20080039362A1 (en) * 2006-08-09 2008-02-14 Afmedica, Inc. Combination drug therapy for reducing scar tissue formation
WO2008027783A2 (en) * 2006-08-29 2008-03-06 Vance Products Incorporated, D/B/A Cook Urological Incorporated Prosthetic testicle
US8072211B2 (en) * 2006-08-30 2011-12-06 Koninklijke Philips Electronics N.V. Multi-channel magnetic resonance imaging and spectroscopy
US8905999B2 (en) * 2006-09-01 2014-12-09 Cardiac Pacemakers, Inc. Method and apparatus for endolymphatic drug delivery
US7780730B2 (en) * 2006-09-25 2010-08-24 Iyad Saidi Nasal implant introduced through a non-surgical injection technique
EP2079385B1 (en) 2006-10-23 2013-11-20 C.R.Bard, Inc. Breast marker
WO2008052136A2 (en) 2006-10-25 2008-05-02 Proteus Biomedical, Inc. Controlled activation ingestible identifier
US8280514B2 (en) * 2006-10-31 2012-10-02 Advanced Neuromodulation Systems, Inc. Identifying areas of the brain by examining the neuronal signals
JP5528810B2 (ja) * 2006-10-31 2014-06-25 コーニンクレッカ フィリップス エヌ ヴェ 消化管において薬品を放出するための飲み込み可能なマルチノズルの投薬デバイス
US9023114B2 (en) 2006-11-06 2015-05-05 Tyrx, Inc. Resorbable pouches for implantable medical devices
US8142805B1 (en) * 2006-11-06 2012-03-27 Clemson University Research Foundation Implantable devices including fixed tissues
EP2079389B1 (en) * 2006-11-06 2018-01-10 Tyrx, Inc. Resorbable pouches for implantable medical devices
US9492596B2 (en) 2006-11-06 2016-11-15 Atrium Medical Corporation Barrier layer with underlying medical device and one or more reinforcing support structures
EP2069004A4 (en) 2006-11-20 2014-07-09 Proteus Digital Health Inc PERSONAL HEALTH SIGNAL RECEIVERS WITH ACTIVE SIGNAL PROCESSING
US8603150B2 (en) 2006-12-04 2013-12-10 Carefusion 2200, Inc. Methods and apparatus for adjusting blood circulation
US9308148B2 (en) 2006-12-04 2016-04-12 Thermatx, Inc. Methods and apparatus for adjusting blood circulation
US9579077B2 (en) 2006-12-12 2017-02-28 C.R. Bard, Inc. Multiple imaging mode tissue marker
US8401622B2 (en) 2006-12-18 2013-03-19 C. R. Bard, Inc. Biopsy marker with in situ-generated imaging properties
CN101686800A (zh) 2007-02-01 2010-03-31 普罗秋斯生物医学公司 可摄入事件标记器系统
WO2008098007A1 (en) * 2007-02-05 2008-08-14 Freedom-2, Inc. Tissue fillers and methods of using the same
WO2008097511A2 (en) 2007-02-07 2008-08-14 Cook Incorporated Medical device coatings for releasing a therapeutic agent at multiple rates
US7813811B2 (en) * 2007-02-08 2010-10-12 Neuropace, Inc. Refillable reservoir lead systems
US7844345B2 (en) * 2007-02-08 2010-11-30 Neuropace, Inc. Drug eluting lead systems
CA2714754A1 (en) * 2007-02-13 2008-08-21 Virender K. Sharma Method and apparatus for electrical stimulation of the pancreatico-biliary system
KR101528748B1 (ko) 2007-02-14 2015-06-15 프로테우스 디지털 헬스, 인코포레이티드 고 표면적 전극을 갖는 체내 전원
FR2913688A1 (fr) * 2007-03-15 2008-09-19 Bluestar Silicones France Soc Article comprenant un gel silicone additive d'un principe actif anti-odeur
EP2129517A4 (en) * 2007-03-26 2012-11-21 Univ Connecticut CHARCOAL NANOCOMPOSITES OF ELECTRO-WIRED APATITE POLYMERS
EP2129339B1 (en) * 2007-03-29 2015-03-04 Tyrx, Inc. Biodegradable, polymer coverings for breast implants
US8642067B2 (en) 2007-04-02 2014-02-04 Allergen, Inc. Methods and compositions for intraocular administration to treat ocular conditions
US20080255612A1 (en) 2007-04-13 2008-10-16 Angiotech Pharmaceuticals, Inc. Self-retaining systems for surgical procedures
ES2562205T3 (es) * 2007-04-17 2016-03-03 Codman & Shurtleff, Inc. Hibrídos de curcumina resveratrol
US8383865B2 (en) * 2007-04-17 2013-02-26 Codman & Shurtleff, Inc. Curcumin derivatives
WO2008147867A2 (en) * 2007-05-23 2008-12-04 Allergan, Inc. Cross-linked collagen and uses thereof
US20110123476A1 (en) * 2007-05-24 2011-05-26 Mbiya Kapiamba Adhesive Formulations
US8540632B2 (en) 2007-05-24 2013-09-24 Proteus Digital Health, Inc. Low profile antenna for in body device
US20080293910A1 (en) * 2007-05-24 2008-11-27 Tyco Healthcare Group Lp Adhesive formulatiions
WO2008149473A1 (ja) * 2007-06-07 2008-12-11 National University Corporation Kanazawa University 心筋パッド
EP2160220A4 (en) * 2007-06-14 2012-07-04 Advanced Neuromodulation Sys ELECTRODE ARRANGEMENTS BASED ON MICROPHONES AND RELEVANT NERVE STIMULATION SYSTEMS, DEVICES AND METHOD
US8617069B2 (en) 2007-06-21 2013-12-31 Abbott Diabetes Care Inc. Health monitor
EP2171031B1 (en) 2007-06-21 2018-12-05 Abbott Diabetes Care Inc. Health management devices and methods
US7858835B2 (en) * 2007-06-27 2010-12-28 Tyco Healthcare Group Lp Foam control for synthetic adhesive/sealant
US8641618B2 (en) 2007-06-27 2014-02-04 Abbott Diabetes Care Inc. Method and structure for securing a monitoring device element
US8085151B2 (en) 2007-06-28 2011-12-27 Abbott Diabetes Care Inc. Signal converting cradle for medical condition monitoring and management system
US8594794B2 (en) 2007-07-24 2013-11-26 Cvrx, Inc. Baroreflex activation therapy with incrementally changing intensity
US8318695B2 (en) * 2007-07-30 2012-11-27 Allergan, Inc. Tunably crosslinked polysaccharide compositions
US8455459B2 (en) 2007-08-02 2013-06-04 Medicis Pharmaceutical Corporation Method of applying an injectable filler
US8706211B2 (en) * 2007-08-17 2014-04-22 The Invention Science Fund I, Llc Systems, devices, and methods including catheters having self-cleaning surfaces
US8734718B2 (en) 2007-08-17 2014-05-27 The Invention Science Fund I, Llc Systems, devices, and methods including catheters having an actively controllable therapeutic agent delivery component
US8702640B2 (en) 2007-08-17 2014-04-22 The Invention Science Fund I, Llc System, devices, and methods including catheters configured to monitor and inhibit biofilm formation
US8753304B2 (en) 2007-08-17 2014-06-17 The Invention Science Fund I, Llc Systems, devices, and methods including catheters having acoustically actuatable waveguide components for delivering a sterilizing stimulus to a region proximate a surface of the catheter
US8460229B2 (en) * 2007-08-17 2013-06-11 The Invention Science Fund I, Llc Systems, devices, and methods including catheters having components that are actively controllable between transmissive and reflective states
US20090048648A1 (en) * 2007-08-17 2009-02-19 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Self-sterilizing device
US8647292B2 (en) 2007-08-17 2014-02-11 The Invention Science Fund I, Llc Systems, devices, and methods including catheters having components that are actively controllable between two or more wettability states
US8366652B2 (en) * 2007-08-17 2013-02-05 The Invention Science Fund I, Llc Systems, devices, and methods including infection-fighting and monitoring shunts
US9005263B2 (en) 2007-08-17 2015-04-14 The Invention Science Fund I, Llc System, devices, and methods including actively-controllable sterilizing excitation delivery implants
US8391970B2 (en) 2007-08-27 2013-03-05 The Feinstein Institute For Medical Research Devices and methods for inhibiting granulocyte activation by neural stimulation
US20130079749A1 (en) * 2007-08-29 2013-03-28 Advanced Bionics, Llc Modular Drug Delivery System for Minimizing Trauma During and After Insertion of a Cochlear Lead
US8271101B2 (en) * 2007-08-29 2012-09-18 Advanced Bionics Modular drug delivery system for minimizing trauma during and after insertion of a cochlear lead
WO2009029866A2 (en) 2007-08-29 2009-03-05 Advanced Bionics, Llc Minimizing trauma during and after insertion of a cochlear lead
WO2009032553A2 (en) * 2007-08-31 2009-03-12 Leon Dejournett Catheter and computerized system for intravenous blood chemistry monitoring
DK2192946T3 (da) 2007-09-25 2022-11-21 Otsuka Pharma Co Ltd Kropsintern anordning med virtuel dipol signalforstærkning
ES2488406T3 (es) 2007-09-27 2014-08-27 Ethicon Llc Suturas de auto-retención que incluyen elementos de retención a tejido con resistencia mejorada
US8697044B2 (en) 2007-10-09 2014-04-15 Allergan, Inc. Crossed-linked hyaluronic acid and collagen and uses thereof
US20090099612A1 (en) * 2007-10-15 2009-04-16 Armstrong Julie S Electrical conductor having a bioerodible coating
US20090259280A1 (en) * 2007-10-15 2009-10-15 Kevin Wilkin Electrical stimulation lead with bioerodible anchors and anchor straps
US8101371B2 (en) 2007-10-18 2012-01-24 Musc Foundation For Research Development Methods for the diagnosis of genitourinary cancer
US7910134B2 (en) 2007-10-29 2011-03-22 Ayman Boutros Alloplastic injectable dermal filler and methods of use thereof
US8475815B2 (en) 2007-10-29 2013-07-02 Ayman Boutros Alloplastic injectable dermal filler and methods of use thereof
US8431141B2 (en) 2007-10-29 2013-04-30 Ayman Boutros Alloplastic injectable dermal filler and methods of use thereof
US8709395B2 (en) 2007-10-29 2014-04-29 Ayman Boutros Method for repairing or replacing damaged tissue
ES2662647T3 (es) * 2007-10-30 2018-04-09 Baxter International Inc. Uso de una biomatriz de colágeno biofuncional regenerativa para tratar defectos viscerales o parietales
US7951393B2 (en) * 2007-11-14 2011-05-31 Canaan Vernon Lavelle Harris Keloid therapy
US20110035004A1 (en) * 2007-11-14 2011-02-10 Maxwell G Interfaced medical implant
HUE042931T2 (hu) 2007-11-16 2019-07-29 Aclaris Therapeutics Inc Kompozíciók és eljárások purpura kezelésére
US20090143348A1 (en) * 2007-11-30 2009-06-04 Ahmet Tezel Polysaccharide gel compositions and methods for sustained delivery of drugs
US8394782B2 (en) 2007-11-30 2013-03-12 Allergan, Inc. Polysaccharide gel formulation having increased longevity
US8394784B2 (en) * 2007-11-30 2013-03-12 Allergan, Inc. Polysaccharide gel formulation having multi-stage bioactive agent delivery
WO2009076412A1 (en) 2007-12-10 2009-06-18 Bayer Healthcare Llc Method of depositing reagent material in a test sensor
US20090287120A1 (en) 2007-12-18 2009-11-19 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Circulatory monitoring systems and methods
US8280484B2 (en) 2007-12-18 2012-10-02 The Invention Science Fund I, Llc System, devices, and methods for detecting occlusions in a biological subject
US8636670B2 (en) 2008-05-13 2014-01-28 The Invention Science Fund I, Llc Circulatory monitoring systems and methods
US9717896B2 (en) 2007-12-18 2017-08-01 Gearbox, Llc Treatment indications informed by a priori implant information
US9672471B2 (en) 2007-12-18 2017-06-06 Gearbox Llc Systems, devices, and methods for detecting occlusions in a biological subject including spectral learning
US20090287101A1 (en) * 2008-05-13 2009-11-19 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Circulatory monitoring systems and methods
US8771313B2 (en) 2007-12-19 2014-07-08 Ethicon, Inc. Self-retaining sutures with heat-contact mediated retainers
US8916077B1 (en) 2007-12-19 2014-12-23 Ethicon, Inc. Self-retaining sutures with retainers formed from molten material
US8118834B1 (en) 2007-12-20 2012-02-21 Angiotech Pharmaceuticals, Inc. Composite self-retaining sutures and method
US8728528B2 (en) 2007-12-20 2014-05-20 Evonik Corporation Process for preparing microparticles having a low residual solvent volume
US8615856B1 (en) 2008-01-30 2013-12-31 Ethicon, Inc. Apparatus and method for forming self-retaining sutures
WO2009097556A2 (en) 2008-01-30 2009-08-06 Angiotech Pharmaceuticals, Inc. Appartaus and method for forming self-retaining sutures
US8311610B2 (en) 2008-01-31 2012-11-13 C. R. Bard, Inc. Biopsy tissue marker
US7745670B2 (en) * 2008-06-27 2010-06-29 Codman & Shurtleff, Inc. Curcumin-Resveratrol hybrid molecule
US9125647B2 (en) 2008-02-21 2015-09-08 Ethicon, Inc. Method and apparatus for elevating retainers on self-retaining sutures
US8641732B1 (en) 2008-02-26 2014-02-04 Ethicon, Inc. Self-retaining suture with variable dimension filament and method
US8293813B2 (en) * 2008-03-05 2012-10-23 Biomet Manufacturing Corporation Cohesive and compression resistant demineralized bone carrier matrix
DK3235491T3 (da) 2008-03-05 2021-02-08 Otsuka Pharma Co Ltd Spiselige hændelsesmarkeringsenheder og systemer med multimodus-kommunikation
EP2252246B1 (en) * 2008-03-14 2014-06-18 Bionumerik Pharmaceuticals, Inc. Chemoprotective methods and compositions
US11730407B2 (en) 2008-03-28 2023-08-22 Dexcom, Inc. Polymer membranes for continuous analyte sensors
US8583204B2 (en) 2008-03-28 2013-11-12 Dexcom, Inc. Polymer membranes for continuous analyte sensors
US8682408B2 (en) 2008-03-28 2014-03-25 Dexcom, Inc. Polymer membranes for continuous analyte sensors
US9662490B2 (en) 2008-03-31 2017-05-30 The Feinstein Institute For Medical Research Methods and systems for reducing inflammation by neuromodulation and administration of an anti-inflammatory drug
WO2009146030A1 (en) 2008-03-31 2009-12-03 The Feinstein Institute For Medical Research Methods and systems for reducing inflammation by neuromodulation of t-cell activity
EP2265324B1 (en) 2008-04-11 2015-01-28 Sanofi-Aventis Deutschland GmbH Integrated analyte measurement system
US8262874B2 (en) * 2008-04-14 2012-09-11 Abbott Diabetes Care Inc. Biosensor coating composition and methods thereof
BRPI0911132B8 (pt) 2008-04-15 2021-06-22 Angiotech Pharm Inc sutura para ser usada em um procedimento aplicado ao tecido
US8326439B2 (en) 2008-04-16 2012-12-04 Nevro Corporation Treatment devices with delivery-activated inflatable members, and associated systems and methods for treating the spinal cord and other tissues
US8263704B2 (en) 2008-04-23 2012-09-11 Tyco Healthcare Group Lp Bioabsorbable surgical composition
US8961560B2 (en) 2008-05-16 2015-02-24 Ethicon, Inc. Bidirectional self-retaining sutures with laser-marked and/or non-laser marked indicia and methods
US9034365B2 (en) 2008-05-20 2015-05-19 Poly-Med, Inc. Biostable, multipurpose, microbicidal intravaginal devices
WO2009143425A1 (en) * 2008-05-22 2009-11-26 The Regents Of The University Of California Membrane precursors and membranes formed therefrom
US7985776B2 (en) * 2008-06-27 2011-07-26 Codman & Shurtleff, Inc. Iontophoretic delivery of curcumin and curcumin analogs for the treatment of Alzheimer's Disease
US20120209396A1 (en) 2008-07-07 2012-08-16 David Myung Orthopedic implants having gradient polymer alloys
SG195535A1 (en) 2008-07-08 2013-12-30 Proteus Digital Health Inc Ingestible event marker data framework
US8450475B2 (en) 2008-08-04 2013-05-28 Allergan, Inc. Hyaluronic acid-based gels including lidocaine
JP5722773B2 (ja) * 2008-08-05 2015-05-27 バイオミメディカ インコーポレイテッド ポリウレタングラフト化ヒドロゲル
US8900431B2 (en) 2008-08-27 2014-12-02 Edwards Lifesciences Corporation Analyte sensor
ES2829971T3 (es) 2008-09-02 2021-06-02 Tautona Group Lp Hilos de ácido hialurónico y/o derivados de los mismos, métodos para fabricar los mismos y usos de los mismos
EP2344215A4 (en) * 2008-09-11 2013-12-18 Bacterin Int Inc ELASTOMERIC ARTICLE COMPRISING A BROAD-SPECTRUM ANTIMICROBIAL AGENT AND PREPARATION METHOD THEREOF
EP2326944B1 (en) 2008-09-19 2020-08-19 Dexcom, Inc. Particle-containing membrane and particulate electrode for analyte sensors
US8419793B2 (en) * 2008-09-19 2013-04-16 Mentor Worldwide Llc Coating with antimicrobial agents
US8420153B2 (en) * 2008-09-19 2013-04-16 Mentor Worldwide Llc Coating with antimicrobial agents
EP2708247B1 (en) * 2008-09-22 2017-06-14 Boston Scientific Neuromodulation Corporation Implantable or insertable medical devices
US9327061B2 (en) 2008-09-23 2016-05-03 Senorx, Inc. Porous bioabsorbable implant
US10603489B2 (en) 2008-10-09 2020-03-31 Virender K. Sharma Methods and apparatuses for stimulating blood vessels in order to control, treat, and/or prevent a hemorrhage
US9079028B2 (en) 2008-10-09 2015-07-14 Virender K. Sharma Method and apparatus for stimulating the vascular system
EP2735284B1 (en) * 2008-10-17 2016-12-07 Allergan, Inc. Prosthetic implant shell
US8417344B2 (en) * 2008-10-24 2013-04-09 Cyberonics, Inc. Dynamic cranial nerve stimulation based on brain state determination from cardiac data
FR2937857B1 (fr) * 2008-10-30 2015-04-03 Brothier Lab Membrane chirurgicale antiadherence
BRPI0921810B8 (pt) 2008-11-03 2021-06-22 Angiotech Pharm Inc montagem para inserir um comprimento de sutura no interior do corpo de um mamífero
GB0820492D0 (en) 2008-11-07 2008-12-17 Sportcell Cell compositions and uses thereof
JP5516414B2 (ja) 2008-11-07 2014-06-11 日立化成株式会社 血清又は血漿分離材及びそれを用いた採血管
CN102215909B (zh) 2008-11-18 2014-09-10 赛博恩特医疗器械公司 优化用于消炎刺激的电极放置的装置和方法
WO2010059586A1 (en) 2008-11-19 2010-05-27 Entrigue Surgical, Inc. Apparatus and methods for correcting nasal valve collapse
US20110160681A1 (en) * 2008-12-04 2011-06-30 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Systems, devices, and methods including catheters having light removable coatings based on a sensed condition
US20110208023A1 (en) * 2008-12-04 2011-08-25 Goodall Eleanor V Systems, devices, and methods including implantable devices with anti-microbial properties
US20110208021A1 (en) * 2008-12-04 2011-08-25 Goodall Eleanor V Systems, devices, and methods including implantable devices with anti-microbial properties
US20110295090A1 (en) 2008-12-04 2011-12-01 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Systems, devices, and methods including implantable devices with anti-microbial properties
US8585627B2 (en) 2008-12-04 2013-11-19 The Invention Science Fund I, Llc Systems, devices, and methods including catheters configured to monitor biofilm formation having biofilm spectral information configured as a data structure
US9895530B2 (en) 2008-12-05 2018-02-20 Spr Therapeutics, Inc. Systems and methods to place one or more leads in tissue to electrically stimulate nerves of passage to treat pain
US10668285B2 (en) 2008-12-05 2020-06-02 Spr Therapeutics, Inc. Systems and methods to place one or more leads in tissue to electrically stimulate nerves to treat pain
US20120150204A1 (en) * 2008-12-15 2012-06-14 Allergan, Inc. Implantable silk prosthetic device and uses thereof
BRPI0805495A2 (pt) * 2008-12-19 2010-09-08 Miranda Jose Maria De implante de silicone com compartimentos expansìveis e/ou interativos, revestido ou não de espuma de poliuretano de ricinus communis e/ou hidroxiapatita, com abas ou cordões de fixação
US20110295240A1 (en) * 2008-12-23 2011-12-01 Ams Research Corporation Foley catheter with proxmity sensor
US20100168851A1 (en) * 2008-12-30 2010-07-01 David Paul Vanderbilt Surface Modified Biomedical Devices
US8670818B2 (en) 2008-12-30 2014-03-11 C. R. Bard, Inc. Marker delivery device for tissue marker placement
SG172846A1 (en) 2009-01-06 2011-08-29 Proteus Biomedical Inc Ingestion-related biofeedback and personalized medical therapy method and system
US8126736B2 (en) 2009-01-23 2012-02-28 Warsaw Orthopedic, Inc. Methods and systems for diagnosing, treating, or tracking spinal disorders
US8685093B2 (en) 2009-01-23 2014-04-01 Warsaw Orthopedic, Inc. Methods and systems for diagnosing, treating, or tracking spinal disorders
US7723515B1 (en) 2009-01-26 2010-05-25 Codman & Shurtleff, Inc. Methylene blue—curcumin analog for the treatment of alzheimer's disease
US20100286585A1 (en) * 2009-01-26 2010-11-11 Codman & Shurtleff, Inc. Shunt Delivery of Curcumin
US9375169B2 (en) 2009-01-30 2016-06-28 Sanofi-Aventis Deutschland Gmbh Cam drive for managing disposable penetrating member actions with a single motor and motor and control system
US20100198034A1 (en) 2009-02-03 2010-08-05 Abbott Diabetes Care Inc. Compact On-Body Physiological Monitoring Devices and Methods Thereof
CN105167888B (zh) 2009-02-24 2018-04-20 史密夫和内修有限公司 用于fai手术的方法和设备
US9244060B2 (en) * 2009-03-26 2016-01-26 Warsaw Orthopedic, Inc. Site localization and methods for monitoring treatment of disturbed blood vessels
US20100249924A1 (en) 2009-03-27 2010-09-30 Allergan, Inc. Bioerodible matrix for tissue involvement
US20100246316A1 (en) * 2009-03-31 2010-09-30 Baxter International Inc. Dispenser, kit and mixing adapter
US20110008406A1 (en) 2009-04-20 2011-01-13 Altman Gregory H Silk Fibroin Hydrogels and Uses Thereof
US8827912B2 (en) 2009-04-24 2014-09-09 Cyberonics, Inc. Methods and systems for detecting epileptic events using NNXX, optionally with nonlinear analysis parameters
US8172759B2 (en) * 2009-04-24 2012-05-08 Cyberonics, Inc. Methods and systems for detecting epileptic events using nonlinear analysis parameters
US8996116B2 (en) 2009-10-30 2015-03-31 Setpoint Medical Corporation Modulation of the cholinergic anti-inflammatory pathway to treat pain or addiction
US8788034B2 (en) 2011-05-09 2014-07-22 Setpoint Medical Corporation Single-pulse activation of the cholinergic anti-inflammatory pathway to treat chronic inflammation
US9211410B2 (en) 2009-05-01 2015-12-15 Setpoint Medical Corporation Extremely low duty-cycle activation of the cholinergic anti-inflammatory pathway to treat chronic inflammation
US10206813B2 (en) 2009-05-18 2019-02-19 Dose Medical Corporation Implants with controlled drug delivery features and methods of using same
WO2010138856A1 (en) 2009-05-29 2010-12-02 Abbott Diabetes Care Inc. Medical device antenna systems having external antenna configurations
US9517023B2 (en) * 2009-06-01 2016-12-13 Profusa, Inc. Method and system for directing a localized biological response to an implant
CN102573986B (zh) 2009-06-09 2016-01-20 赛博恩特医疗器械公司 用于无导线刺激器的具有袋部的神经封套
WO2010151269A1 (en) * 2009-06-26 2010-12-29 Biotic Laboratories, Inc. Para-xylylene based multilayer drug elution devices
US9351677B2 (en) 2009-07-02 2016-05-31 Dexcom, Inc. Analyte sensor with increased reference capacity
US20110027458A1 (en) 2009-07-02 2011-02-03 Dexcom, Inc. Continuous analyte sensors and methods of making same
US20110029076A1 (en) * 2009-07-30 2011-02-03 Paletta John D Breast Implant Therapeutic Delivery System
US20110038910A1 (en) 2009-08-11 2011-02-17 Atrium Medical Corporation Anti-infective antimicrobial-containing biomaterials
US9440005B2 (en) * 2009-08-21 2016-09-13 National Institute Of Agrobiological Sciences Substrate for feeding cells and/or tissues, cell/tissue-feeder and method for the production of the same, method for the regeneration of tissues, and method for the production of porous bodies
EP2473963A4 (en) 2009-08-31 2014-01-08 Abbott Diabetes Care Inc MEDICAL DEVICES AND METHOD
TWI517050B (zh) 2009-11-04 2016-01-11 普羅托斯數位健康公司 供應鏈管理之系統
EP2498798A4 (en) * 2009-11-10 2014-01-01 Univ Columbia COMPOSITIONS AND METHODS OF WOUND TREATMENT
US11051744B2 (en) 2009-11-17 2021-07-06 Setpoint Medical Corporation Closed-loop vagus nerve stimulation
US9833621B2 (en) 2011-09-23 2017-12-05 Setpoint Medical Corporation Modulation of sirtuins by vagus nerve stimulation
WO2011061733A1 (en) * 2009-11-17 2011-05-26 Israel Shamir Lebovitz A method and device for remote controlled application of medical monitoring and attention
EP3636314B1 (en) 2009-12-23 2021-09-08 Setpoint Medical Corporation Neural stimulation devices and systems for treatment of chronic inflammation
WO2011085047A1 (en) 2010-01-05 2011-07-14 The Regents Of The University Of California Droplet bilayer formation using throughput liquid handling techniques
US8641661B2 (en) 2010-01-05 2014-02-04 Baxter International Inc. Mixing system, kit and mixer adapter
US8771329B2 (en) 2010-01-08 2014-07-08 Carefusion 2200, Inc. Methods and apparatus for enhancing vascular access in an appendage to enhance therapeutic and interventional procedures
CA2726566A1 (en) * 2010-01-11 2011-07-11 Baxter International Inc. Pipette system, pipette tip assembly and kit
US20110171286A1 (en) * 2010-01-13 2011-07-14 Allergan, Inc. Hyaluronic acid compositions for dermatological use
US20110172180A1 (en) 2010-01-13 2011-07-14 Allergan Industrie. Sas Heat stable hyaluronic acid compositions for dermatological use
US9114188B2 (en) 2010-01-13 2015-08-25 Allergan, Industrie, S.A.S. Stable hydrogel compositions including additives
US20110171311A1 (en) * 2010-01-13 2011-07-14 Allergan Industrie, Sas Stable hydrogel compositions including additives
US9138308B2 (en) 2010-02-03 2015-09-22 Apollo Endosurgery, Inc. Mucosal tissue adhesion via textured surface
US8828668B2 (en) 2010-02-11 2014-09-09 The Board Of Trustees Of The Leland Stanford Junior University Markers for determination of patient responsiveness
CA2792729C (en) 2010-03-12 2016-06-28 Allergan Industrie, Sas Fluid compositions for improving skin conditions
WO2011113507A2 (en) * 2010-03-15 2011-09-22 Ulrich Dietz Use of nitrocarboxylic acids for the treatment, diagnosis and prophylaxis of aggressive healing patterns
DK2550027T4 (da) 2010-03-22 2019-05-13 Allergan Inc Tværbundne polysaccharid- og protein-polysaccharid-hydrogeler til blødvævsforøgelse
US8965476B2 (en) 2010-04-16 2015-02-24 Sanofi-Aventis Deutschland Gmbh Tissue penetration device
EP2563851A1 (en) * 2010-04-27 2013-03-06 Allergan, Inc. Foam-like materials and methods for producing same
US8815228B2 (en) 2010-04-30 2014-08-26 Ayman Boutros Alloplastic injectable dermal filler and methods of use thereof
WO2011140283A2 (en) 2010-05-04 2011-11-10 Angiotech Pharmaceuticals, Inc. Self-retaining systems having laser-cut retainers
WO2011143206A2 (en) 2010-05-10 2011-11-17 Allergan, Inc. Porous materials, methods of making and uses
EP2571543B1 (en) 2010-05-11 2018-12-05 Allergan, Inc. Porous materials, methods of making and uses
CA2799201C (en) 2010-05-11 2016-09-20 Allergan, Inc. Porogen compositions, methods of making and uses
US9352003B1 (en) 2010-05-14 2016-05-31 Musculoskeletal Transplant Foundation Tissue-derived tissuegenic implants, and methods of fabricating and using same
US8883210B1 (en) 2010-05-14 2014-11-11 Musculoskeletal Transplant Foundation Tissue-derived tissuegenic implants, and methods of fabricating and using same
CN103002921A (zh) 2010-05-14 2013-03-27 马林克罗特有限公司 用于联合的光学成像和治疗的功能性交联纳米结构
US10130736B1 (en) 2010-05-14 2018-11-20 Musculoskeletal Transplant Foundation Tissue-derived tissuegenic implants, and methods of fabricating and using same
US8945156B2 (en) 2010-05-19 2015-02-03 University Of Utah Research Foundation Tissue fixation
US8858577B2 (en) 2010-05-19 2014-10-14 University Of Utah Research Foundation Tissue stabilization system
TWI557672B (zh) 2010-05-19 2016-11-11 波提亞斯數位康健公司 用於從製造商跟蹤藥物直到患者之電腦系統及電腦實施之方法、用於確認將藥物給予患者的設備及方法、患者介面裝置
US10010272B2 (en) 2010-05-27 2018-07-03 Profusa, Inc. Tissue-integrating electronic apparatus
US10463287B2 (en) 2010-10-06 2019-11-05 Profusa, Inc. Tissue-integrating sensors
AU2011265232B2 (en) 2010-06-11 2015-01-22 Ethicon Llc Suture delivery tools for endoscopic and robot-assisted surgery and methods
WO2011159663A1 (en) 2010-06-16 2011-12-22 Allergan, Inc. Open-cell surface foam materials
US8979877B2 (en) * 2010-07-02 2015-03-17 Neurodynamics, LLC Catheter for use in revascularization procedures and method of using same
WO2012009707A2 (en) 2010-07-16 2012-01-19 Atrium Medical Corporation Composition and methods for altering the rate of hydrolysis of cured oil-based materials
US8883139B2 (en) 2010-08-19 2014-11-11 Allergan Inc. Compositions and soft tissue replacement methods
EP2605762A1 (en) * 2010-08-19 2013-06-26 Allergan, Inc. Compositions comprising adipose tissue and a pge2 analogue and their use in the treatment of a soft tissue condition
US8741281B2 (en) * 2010-08-19 2014-06-03 Allergan, Inc. Compositions and soft tissue replacement methods
US8697057B2 (en) 2010-08-19 2014-04-15 Allergan, Inc. Compositions and soft tissue replacement methods
US8889123B2 (en) 2010-08-19 2014-11-18 Allergan, Inc. Compositions and soft tissue replacement methods
US9005605B2 (en) 2010-08-19 2015-04-14 Allergan, Inc. Compositions and soft tissue replacement methods
ES2713515T3 (es) 2010-08-25 2019-05-22 Tyrx Inc Recubrimientos novedosos para dispositivos médicos
CN103179922B (zh) 2010-08-26 2016-08-17 史密夫和内修有限公司 用于股骨髋臼撞击手术的植入物、外科手术方法和器械
AU2011293169A1 (en) 2010-08-27 2013-03-21 Biomimedica, Inc. Hydrophobic and hydrophilic interpenetrating polymer networks derived from hydrophobic polymers and methods of preparing the same
US8805519B2 (en) 2010-09-30 2014-08-12 Nevro Corporation Systems and methods for detecting intrathecal penetration
EP2625263B1 (en) 2010-10-08 2020-03-11 Terumo BCT, Inc. Configurable methods and systems of growing and harvesting cells in a hollow fiber bioreactor system
JP2014504894A (ja) 2010-11-03 2014-02-27 アンジオテック ファーマシューティカルズ， インコーポレイテッド 薬剤を溶出する留置縫合材及びこれに関する方法
US9675341B2 (en) 2010-11-09 2017-06-13 Ethicon Inc. Emergency self-retaining sutures and packaging
US8788047B2 (en) 2010-11-11 2014-07-22 Spr Therapeutics, Llc Systems and methods for the treatment of pain through neural fiber stimulation
US8788046B2 (en) 2010-11-11 2014-07-22 Spr Therapeutics, Llc Systems and methods for the treatment of pain through neural fiber stimulation
US8788048B2 (en) 2010-11-11 2014-07-22 Spr Therapeutics, Llc Systems and methods for the treatment of pain through neural fiber stimulation
US9585988B2 (en) 2010-11-12 2017-03-07 Tyrx, Inc. Anchorage devices comprising an active pharmaceutical ingredient
US9861814B2 (en) * 2010-12-23 2018-01-09 Medtronic, Inc. Medical electrical lead having biological surface and methods of making and using same
US8846040B2 (en) 2010-12-23 2014-09-30 Rani Therapeutics, Llc Therapeutic agent preparations comprising etanercept for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
WO2012094708A1 (en) * 2011-01-12 2012-07-19 The University Of Queensland Bone graft biomaterial
US8852214B2 (en) 2011-02-04 2014-10-07 University Of Utah Research Foundation System for tissue fixation to bone
CA3115682A1 (en) 2011-02-28 2012-11-15 Abbott Diabetes Care Inc. Devices, systems, and methods associated with analyte monitoring devices and devices incorporating the same
EP2967665B1 (en) 2011-02-28 2020-03-25 Tissue Regeneration Systems, Inc. Modular tissue scaffolds
JP6125488B2 (ja) 2011-03-23 2017-05-10 エシコン・エルエルシーＥｔｈｉｃｏｎ ＬＬＣ 自己保持可変ループ縫合材
US20120259413A1 (en) * 2011-04-07 2012-10-11 Allergan, Inc. Devices, compositions and methods utilizing ep4 and ep2 receptor agonists for preventing, reducing or treating capsular contracture
US8834928B1 (en) 2011-05-16 2014-09-16 Musculoskeletal Transplant Foundation Tissue-derived tissugenic implants, and methods of fabricating and using same
EP3536307B1 (en) 2011-06-03 2021-10-20 ALLERGAN Industrie, SAS Dermal filler compositions including antioxidants
US20130096081A1 (en) 2011-06-03 2013-04-18 Allergan, Inc. Dermal filler compositions
US9408797B2 (en) 2011-06-03 2016-08-09 Allergan, Inc. Dermal filler compositions for fine line treatment
US9393263B2 (en) 2011-06-03 2016-07-19 Allergan, Inc. Dermal filler compositions including antioxidants
US20130172931A1 (en) 2011-06-06 2013-07-04 Jeffrey M. Gross Methods and devices for soft palate tissue elevation procedures
US10245178B1 (en) 2011-06-07 2019-04-02 Glaukos Corporation Anterior chamber drug-eluting ocular implant
WO2012174049A2 (en) * 2011-06-13 2012-12-20 The General Hospital Corporation Compositions and methods for controlling neuronal excitation
US9756874B2 (en) 2011-07-11 2017-09-12 Proteus Digital Health, Inc. Masticable ingestible product and communication system therefor
WO2015112603A1 (en) 2014-01-21 2015-07-30 Proteus Digital Health, Inc. Masticable ingestible product and communication system therefor
WO2013011511A1 (en) 2011-07-18 2013-01-24 Mor Research Applications Ltd. A device for adjusting the intraocular pressure
BR112014001397A2 (pt) 2011-07-21 2017-02-21 Proteus Biomedical Inc dispositivo, sistema e método de comunicação móvel
WO2013018088A1 (en) 2011-08-04 2013-02-07 Ramot At Tel-Aviv University Ltd Il-1 receptor antagonist-coated electrode and uses thereof
WO2013021357A1 (en) * 2011-08-08 2013-02-14 Ecole Polytechnique Federale De Lausanne (Epfl) In-vivo condition monitoring of metallic implants by electrochemical techniques
US20130244943A1 (en) 2011-09-06 2013-09-19 Allergan, Inc. Hyaluronic acid-collagen matrices for dermal filling and volumizing applications
US9662422B2 (en) 2011-09-06 2017-05-30 Allergan, Inc. Crosslinked hyaluronic acid-collagen gels for improving tissue graft viability and soft tissue augmentation
EP4193907A1 (en) 2011-09-13 2023-06-14 Glaukos Corporation Intraocular physiological sensor
EP2763707B1 (en) 2011-10-03 2018-03-28 Hyalex Orthopaedics, Inc. Polymeric adhesive for anchoring compliant materials to another surface
US9150598B2 (en) 2011-10-05 2015-10-06 The Regents Of The University Of California Masking apertures enabling automation and solution exchange in sessile bilayers
US9069536B2 (en) 2011-10-31 2015-06-30 Abbott Diabetes Care Inc. Electronic devices having integrated reset systems and methods thereof
AU2012340699A1 (en) 2011-11-21 2014-06-19 Biomimedica, Inc. Systems, devices, and methods for anchoring orthopaedic implants to bone
AU2013211937B2 (en) 2012-01-25 2016-07-28 Nevro Corporation Lead anchors and associated systems and methods
EP2814517A1 (en) * 2012-02-15 2014-12-24 Microarray Limited Wound screen
US20130245759A1 (en) * 2012-03-09 2013-09-19 The Florida International University Board Of Trustees Medical devices incorporating silicone nanoparticles, and uses thereof
US9572983B2 (en) 2012-03-26 2017-02-21 Setpoint Medical Corporation Devices and methods for modulation of bone erosion
CA2814283A1 (en) * 2012-04-24 2013-10-24 The Royal Institution For The Advancement Of Learning/Mcgill University Methods and systems for closed loop neurotrophic delivery microsystems
US9645111B2 (en) 2012-06-08 2017-05-09 Medtronic Minimed, Inc. Application of electrochemical impedance spectroscopy in sensor systems, devices, and related methods
US9867880B2 (en) 2012-06-13 2018-01-16 Atrium Medical Corporation Cured oil-hydrogel biomaterial compositions for controlled drug delivery
US11957334B2 (en) 2012-07-30 2024-04-16 Conextions, Inc. Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone
US10219804B2 (en) 2012-07-30 2019-03-05 Conextions, Inc. Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone
US11944531B2 (en) 2012-07-30 2024-04-02 Conextions, Inc. Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone
US11253252B2 (en) 2012-07-30 2022-02-22 Conextions, Inc. Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone
US9629632B2 (en) 2012-07-30 2017-04-25 Conextions, Inc. Soft tissue repair devices, systems, and methods
US10835241B2 (en) 2012-07-30 2020-11-17 Conextions, Inc. Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone
US9427309B2 (en) 2012-07-30 2016-08-30 Conextions, Inc. Soft tissue repair devices, systems, and methods
US10390935B2 (en) 2012-07-30 2019-08-27 Conextions, Inc. Soft tissue to bone repair devices, systems, and methods
WO2014022657A1 (en) 2012-08-02 2014-02-06 Allergan, Inc. Mucosal tissue adhesion via textured surface
MX2015001673A (es) * 2012-08-06 2015-08-14 South Dakota Board Of Regents Dispositivo medico implantable de elucion direccional.
WO2014027042A2 (en) * 2012-08-17 2014-02-20 Amsilk Gmbh Use of self-assembling polypeptides as tissue adhesives
US9144678B2 (en) * 2012-09-19 2015-09-29 Ohio State Innovation Foundation Apparatus, systems, and methods for treating body organ aging
EP2897658A1 (en) 2012-09-24 2015-07-29 Allergan, Inc. Porous materials, methods of making and uses
WO2014052724A1 (en) 2012-09-28 2014-04-03 Allergan, Inc. Porogen compositions, methods of making and uses
WO2014169301A1 (en) * 2013-04-12 2014-10-16 Bui The Duy Systems and methods for delivering cross-linked halyuronic acid into a patient
US9949692B2 (en) 2012-12-21 2018-04-24 Canary Medical Inc. Stent graft monitoring assembly and method of use thereof
PT2961350T (pt) 2013-02-27 2018-05-09 Spirox Inc Implantes nasais e sistemas
US9730638B2 (en) 2013-03-13 2017-08-15 Glaukos Corporation Intraocular physiological sensor
AU2014241420B2 (en) 2013-03-14 2018-05-31 Profusa, Inc. Method and device for correcting optical signals
WO2014144070A1 (en) 2013-03-15 2014-09-18 Hunter William L Stent monitoring assembly and method of use thereof
ES2910362T3 (es) 2013-03-15 2022-05-12 Canary Medical Inc Dispositivos, sistemas y métodos para monitorizar reemplazos de cadera
JP6511439B2 (ja) 2013-06-04 2019-05-15 プロテウス デジタル ヘルス， インコーポレイテッド データ収集および転帰の査定のためのシステム、装置、および方法
CA2913474C (en) 2013-06-06 2023-04-18 William A. Mcmillan Apparatus and methods for detecting optical signals from implanted sensors
US9265935B2 (en) 2013-06-28 2016-02-23 Nevro Corporation Neurological stimulation lead anchors and associated systems and methods
US9341639B2 (en) 2013-07-26 2016-05-17 Industrial Technology Research Institute Apparatus for microfluid detection
MX2016001247A (es) 2013-07-30 2016-08-17 Musculoskeletal Transplant Foundation Matrices derivadas de tejido suave acelular y metodos para preparar las mismas.
DK3035849T3 (da) * 2013-08-21 2019-09-30 Senseonics Inc Lægemiddeleluering til beskyttelse in vivo af biosensor-analysander
USD716451S1 (en) 2013-09-24 2014-10-28 C. R. Bard, Inc. Tissue marker for intracorporeal site identification
USD716450S1 (en) 2013-09-24 2014-10-28 C. R. Bard, Inc. Tissue marker for intracorporeal site identification
USD715442S1 (en) 2013-09-24 2014-10-14 C. R. Bard, Inc. Tissue marker for intracorporeal site identification
USD715942S1 (en) 2013-09-24 2014-10-21 C. R. Bard, Inc. Tissue marker for intracorporeal site identification
EP3052117B1 (en) 2013-10-02 2020-04-22 Albert Einstein College of Medicine Methods and compositions to inhibit metastasis and to treat fibrosis and to enhance wound healing
US10084880B2 (en) 2013-11-04 2018-09-25 Proteus Digital Health, Inc. Social media networking based on physiologic information
JP6633522B2 (ja) 2013-11-16 2020-01-22 テルモ ビーシーティー、インコーポレーテッド バイオリアクターにおける細胞増殖
US9539231B2 (en) 2014-01-17 2017-01-10 The Regents Of The University Of Colorado, A Body Corporate Method for treating triple-negative breast cancer using AMPI-109
US11583384B2 (en) 2014-03-12 2023-02-21 Conextions, Inc. Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone
US11008547B2 (en) 2014-03-25 2021-05-18 Terumo Bct, Inc. Passive replacement of media
US10022475B2 (en) * 2014-05-01 2018-07-17 Bao Tran Body augmentation device
JP6655610B2 (ja) 2014-05-29 2020-02-26 グローコス コーポレーション 制御された薬物送達機能を備えるインプラント及びそれを使用する方法
EP2959936B1 (fr) * 2014-06-25 2021-03-31 Sorin CRM SAS Capsule inplantable à fixation par vissage, notamment capsule autonome de stimulation cardiaque
WO2015200722A2 (en) 2014-06-25 2015-12-30 Parker, David, W. Devices, systems and methods for using and monitoring orthopedic hardware
EP4212113A1 (en) 2014-06-25 2023-07-19 Canary Medical Switzerland AG Devices monitoring spinal implants
CA2992263A1 (en) 2014-06-25 2015-12-30 Canary Medical Inc. Devices, systems and methods for using and monitoring tubes in body passageways
JP6656227B2 (ja) 2014-08-26 2020-03-04 スピロックス, インク.Spirox, Inc. 鼻インプラントと使用システム及び使用方法
WO2016044651A1 (en) 2014-09-17 2016-03-24 Canary Medical Inc. Devices, systems and methods for using and monitoring medical devices
JP6830059B2 (ja) 2014-09-26 2021-02-17 テルモ ビーシーティー、インコーポレーテッド スケジュール化された細胞フィーディング
ES2761558T3 (es) 2014-09-30 2020-05-20 Allergan Ind Sas Composiciones de hidrogel estables que incluyen aditivos
US11311725B2 (en) 2014-10-24 2022-04-26 Setpoint Medical Corporation Systems and methods for stimulating and/or monitoring loci in the brain to treat inflammation and to enhance vagus nerve stimulation
US11406833B2 (en) 2015-02-03 2022-08-09 Setpoint Medical Corporation Apparatus and method for reminding, prompting, or alerting a patient with an implanted stimulator
WO2016128783A1 (en) 2015-02-09 2016-08-18 Allergan Industrie Sas Compositions and methods for improving skin appearance
EP3297694A1 (en) 2015-05-21 2018-03-28 Musculoskeletal Transplant Foundation Modified demineralized cortical bone fibers
US20180192939A1 (en) * 2015-07-02 2018-07-12 Mirus Llc Medical devices with integrated sensors and method of production
WO2017004592A1 (en) 2015-07-02 2017-01-05 Terumo Bct, Inc. Cell growth with mechanical stimuli
KR101850607B1 (ko) * 2015-07-23 2018-04-19 서울대학교산학협력단 인돌리지노[3,2-ｃ]퀴놀린계 형광 프로브
US10912864B2 (en) 2015-07-24 2021-02-09 Musculoskeletal Transplant Foundation Acellular soft tissue-derived matrices and methods for preparing same
US11077228B2 (en) 2015-08-10 2021-08-03 Hyalex Orthopaedics, Inc. Interpenetrating polymer networks
US11052175B2 (en) 2015-08-19 2021-07-06 Musculoskeletal Transplant Foundation Cartilage-derived implants and methods of making and using same
WO2017040853A1 (en) 2015-09-02 2017-03-09 Glaukos Corporation Drug delivery implants with bi-directional delivery capacity
WO2017053885A1 (en) 2015-09-25 2017-03-30 Glaukos Corporation Punctal implants with controlled drug delivery features and methods of using same
AU2016326676B2 (en) * 2015-09-25 2021-07-08 Spirox, Inc. Nasal implants and systems and method of use
CA3004745A1 (en) * 2015-11-12 2017-05-18 University Of Virginia Patent Foundation Compositions and methods for vas-occlusive contraception and reversal thereof
US9949821B2 (en) 2015-12-22 2018-04-24 Biosense Webster (Israel) Ltd. Colored silicone for implant safety
US10596367B2 (en) 2016-01-13 2020-03-24 Setpoint Medical Corporation Systems and methods for establishing a nerve block
WO2017127758A1 (en) 2016-01-20 2017-07-27 Setpoint Medical Corporation Implantable microstimulators and inductive charging systems
CN114904142A (zh) 2016-01-20 2022-08-16 赛博恩特医疗器械公司 迷走神经刺激的控制
US11471681B2 (en) 2016-01-20 2022-10-18 Setpoint Medical Corporation Batteryless implantable microstimulators
US10583304B2 (en) 2016-01-25 2020-03-10 Setpoint Medical Corporation Implantable neurostimulator having power control and thermal regulation and methods of use
US10722484B2 (en) * 2016-03-09 2020-07-28 K-Gen, Inc. Methods of cancer treatment
KR20230152788A (ko) 2016-03-23 2023-11-03 카나리 메디칼 아이엔씨. 경보 임플란트를 위한 이식 가능한 리포팅 프로세서
JP7003110B2 (ja) 2016-04-20 2022-01-20 ドーズ メディカル コーポレーション 生体吸収性眼球薬物送達デバイス
US10987133B2 (en) 2016-05-02 2021-04-27 Entellus Medical, Inc. Nasal valve implants and methods of implanting the same
EP3464565A4 (en) 2016-05-25 2020-01-01 Terumo BCT, Inc. CELL EXPANSION
US11685883B2 (en) 2016-06-07 2023-06-27 Terumo Bct, Inc. Methods and systems for coating a cell growth surface
US11104874B2 (en) 2016-06-07 2021-08-31 Terumo Bct, Inc. Coating a bioreactor
WO2018009912A1 (en) * 2016-07-07 2018-01-11 The Regents Of The University Of California Implants using ultrasonic waves for stimulating tissue
CA3030759C (en) * 2016-07-14 2023-07-25 Hollister Incorporated Hygienic medical devices having hydrophilic coatings and methods of forming the same
MX2019000888A (es) 2016-07-22 2019-06-03 Proteus Digital Health Inc Percepcion y deteccion electromagnetica de marcadores de evento ingeribles.
CA3035194A1 (en) 2016-08-26 2018-03-01 Joseph W. Boggs Devices and methods for delivery of electrical current for pain relief
US11696822B2 (en) 2016-09-28 2023-07-11 Conextions, Inc. Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone
US11540973B2 (en) 2016-10-21 2023-01-03 Spr Therapeutics, Llc Method and system of mechanical nerve stimulation for pain relief
US20180140410A1 (en) * 2016-11-21 2018-05-24 William A. Brennan Cosmetic implant
US11331018B2 (en) 2016-12-22 2022-05-17 Profusa, Inc. System and single-channel biosensor for and method of determining analyte value
CN106913952B (zh) * 2017-02-21 2020-08-25 东华大学 一种单纱医用多功能鼻塞及其制备方法
AU2018231031B2 (en) 2017-03-09 2023-11-02 Nevro Corp. Paddle leads and delivery tools, and associated systems and methods
WO2018183624A1 (en) * 2017-03-29 2018-10-04 The Regents Of The University Of Colorado, A Body Corporate Reverse thermal gels and their use as vascular embolic repair agents
CN117247899A (zh) 2017-03-31 2023-12-19 泰尔茂比司特公司 细胞扩增
US11624046B2 (en) 2017-03-31 2023-04-11 Terumo Bct, Inc. Cell expansion
US11173307B2 (en) 2017-08-14 2021-11-16 Setpoint Medical Corporation Vagus nerve stimulation pre-screening test
US11723579B2 (en) 2017-09-19 2023-08-15 Neuroenhancement Lab, LLC Method and apparatus for neuroenhancement
US11717686B2 (en) 2017-12-04 2023-08-08 Neuroenhancement Lab, LLC Method and apparatus for neuroenhancement to facilitate learning and performance
US20210170168A1 (en) * 2017-12-08 2021-06-10 Vomaris Innovations, Inc. Implantable bioelectric devices and methods of use
US11547397B2 (en) 2017-12-20 2023-01-10 Conextions, Inc. Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone
WO2019133997A1 (en) 2017-12-31 2019-07-04 Neuroenhancement Lab, LLC System and method for neuroenhancement to enhance emotional response
JP2021514288A (ja) 2018-02-20 2021-06-10 コネクションズ, インク.Conextions, Inc. 軟質組織を修復し、軟質組織を骨に取り付けるための装置、システム、および方法
WO2019191423A1 (en) 2018-03-29 2019-10-03 Nevro Corp. Leads having sidewall openings, and associated systems and methods
US11364361B2 (en) 2018-04-20 2022-06-21 Neuroenhancement Lab, LLC System and method for inducing sleep by transplanting mental states
US11083563B2 (en) 2018-05-22 2021-08-10 Biosense Webster (Israel) Ltd. Lightweight breast implant
US10869950B2 (en) 2018-07-17 2020-12-22 Hyalex Orthopaedics, Inc. Ionic polymer compositions
EP3849410A4 (en) 2018-09-14 2022-11-02 Neuroenhancement Lab, LLC SLEEP ENHANCEMENT SYSTEM AND METHOD
US11260229B2 (en) 2018-09-25 2022-03-01 The Feinstein Institutes For Medical Research Methods and apparatuses for reducing bleeding via coordinated trigeminal and vagal nerve stimulation
WO2020089016A1 (en) 2018-10-30 2020-05-07 F. Hoffmann-La Roche Ag Implantation needle and kit
AU2019380413A1 (en) 2018-11-13 2021-05-20 Contraline, Inc. Systems and methods for delivering biomaterials
CN109930209B (zh) * 2019-03-07 2022-02-15 华南理工大学 一种具高结晶度及长径比双膦酸盐晶体及其制备方法
CN110174332B (zh) * 2019-05-28 2021-11-09 中国工程物理研究院激光聚变研究中心 一种测试乳粒聚并难易程度的方法
CN110123819B (zh) * 2019-06-03 2022-03-15 南阳南石医院 一种用于治疗疤痕的药物和装置
EP3993715B1 (en) 2019-07-04 2024-04-17 F. Hoffmann-La Roche AG Implantation needle for inserting a subcutaneously insertable element into a body tissue
US11065461B2 (en) 2019-07-08 2021-07-20 Bioness Inc. Implantable power adapter
CN110279887B (zh) * 2019-07-18 2021-12-14 王月玲 一种多用途光子冷凝胶及其制备方法
US11555889B2 (en) * 2020-04-28 2023-01-17 Bae Systems Information And Electronic Systems Integration Inc. Interferometrics for mesa radar
KR20230012585A (ko) 2020-05-21 2023-01-26 더 파인스타인 인스티튜츠 포 메디칼 리서치 미주 신경 자극을 위한 시스템들 및 방법들
US20210378947A1 (en) * 2020-06-03 2021-12-09 Northeastern University Biodegradable Implant for Sustained Trans-Nasal Delivery of Therapeutic Agents to the Brain
CN111939377B (zh) * 2020-08-21 2021-05-14 吉林大学 一种小儿神经护理用新型头皮静脉留置针
CN112244850B (zh) * 2020-09-29 2022-03-25 中国科学院上海微系统与信息技术研究所 一种颅内深部电极记录器件及其制备方法、系统
JP2024515220A (ja) * 2021-04-26 2024-04-05 セラニーズ・イーブイエイ・パフォーマンス・ポリマーズ・エルエルシー 高分子薬剤化合物の持続放出用の埋め込み型デバイス
EP4356398A1 (en) 2021-06-14 2024-04-24 Preh Holding, LLC Connected body surface care module
CN113425682A (zh) * 2021-08-03 2021-09-24 宁夏医科大学 一种药物靶向聚合胶束及其制备方法和应用
CN114805815B (zh) * 2022-05-06 2023-04-11 重庆米克智业科技有限公司 一种端嘌呤基有机硅化合物及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5411527A (en) * 1989-05-03 1995-05-02 Intermedics, Inc. Difibrillation electrodes and implantation
WO2002036054A1 (en) * 2000-11-06 2002-05-10 Afmedica, Inc. Surgically implanted devices having reduced scar tissue
US20030068297A1 (en) * 2001-08-18 2003-04-10 Deepak Jain Composition and methods for skin rejuvenation and repair

Family Cites Families (171)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4215062A (en) * 1978-05-22 1980-07-29 University Of Kansas Endowment Association Anthracycline synthesis
US4296105A (en) * 1978-08-03 1981-10-20 Institut International De Pathologie Cellulaire Et Moleculaire Derivatives of doxorubicine, their preparation and use
US4506690A (en) * 1979-10-15 1985-03-26 The Garrett Corporation Pressure regulator system
CA1174284A (en) * 1980-09-02 1984-09-11 Medtronic, Inc. Body implantable lead
US4534899A (en) * 1981-07-20 1985-08-13 Lipid Specialties, Inc. Synthetic phospholipid compounds
US4506680A (en) * 1983-03-17 1985-03-26 Medtronic, Inc. Drug dispensing body implantable lead
US4888176A (en) * 1984-05-21 1989-12-19 Massachusetts Institute Of Technology Controlled drug delivery high molecular weight polyanhydrides
DE3323025A1 (de) * 1983-06-25 1985-01-10 Hoechst Ag, 6230 Frankfurt Anthracyclin-derivate, ein mikrobiologisches verfahren zu ihrer herstellung und ihre verwendung als cytostatika
GB8319766D0 (en) * 1983-07-22 1983-08-24 Graham N B Controlled release device
US4538616A (en) * 1983-07-25 1985-09-03 Robert Rogoff Blood sugar level sensing and monitoring transducer
US4500676A (en) * 1983-12-15 1985-02-19 Biomatrix, Inc. Hyaluronate modified polymeric articles
US4891225A (en) * 1984-05-21 1990-01-02 Massachusetts Institute Of Technology Bioerodible polyanhydrides for controlled drug delivery
US5266563A (en) * 1984-06-11 1993-11-30 Biomatrix, Inc. Hyakyribate-poly (ethylene oxide) mixtures
US4629623A (en) * 1984-06-11 1986-12-16 Biomatrix, Inc. Hyaluronate-poly (ethylene oxide) compositions and cosmetic formulations thereof
US4636524A (en) * 1984-12-06 1987-01-13 Biomatrix, Inc. Cross-linked gels of hyaluronic acid and products containing such gels
US4582865A (en) * 1984-12-06 1986-04-15 Biomatrix, Inc. Cross-linked gels of hyaluronic acid and products containing such gels
US5128326A (en) * 1984-12-06 1992-07-07 Biomatrix, Inc. Drug delivery systems based on hyaluronans derivatives thereof and their salts and methods of producing same
US4606118A (en) * 1985-02-27 1986-08-19 Medtronic, Inc. Method of making a drug dispensing body
US5099013A (en) * 1985-03-12 1992-03-24 Biomatrix, Inc, Hylan preparation and method of recovery thereof from animal tissues
US4713448A (en) * 1985-03-12 1987-12-15 Biomatrix, Inc. Chemically modified hyaluronic acid preparation and method of recovery thereof from animal tissues
US4714703A (en) * 1985-09-11 1987-12-22 Burckhalter Joseph H Method of inhibiting herpetic lesions
US4882168A (en) * 1986-09-05 1989-11-21 American Cyanamid Company Polyesters containing alkylene oxide blocks as drug delivery systems
US4844099A (en) * 1986-11-24 1989-07-04 Telectronics, N.V. Porous pacemaker electrode tip using a porous substrate
US5403585A (en) * 1987-01-12 1995-04-04 Genentech, Inc. Therapeutic use of enkephalinase
US6387379B1 (en) * 1987-04-10 2002-05-14 University Of Florida Biofunctional surface modified ocular implants, surgical instruments, medical devices, prostheses, contact lenses and the like
US4913743A (en) * 1987-04-15 1990-04-03 Biomatrix, Inc. Processes for managing keratinous material using glycosaminoglycan and cationic polymer combinations
US4795741A (en) * 1987-05-06 1989-01-03 Biomatrix, Inc. Compositions for therapeutic percutaneous embolization and the use thereof
US4882865A (en) * 1988-01-21 1989-11-28 Andeweg Frits J Light-animated graphics display
US6261271B1 (en) * 1989-01-18 2001-07-17 Becton Dickinson And Company Anti-infective and antithrombogenic medical articles and method for their preparation
US4953864A (en) * 1989-06-21 1990-09-04 Daniel Katz Method and apparatus for chance controlled formation of a symbol
US5002067A (en) * 1989-08-23 1991-03-26 Medtronic, Inc. Medical electrical lead employing improved penetrating electrode
US4972848A (en) * 1989-08-23 1990-11-27 Medtronic, Inc. Medical electrical lead with polymeric monolithic controlled release device and method of manufacture
US5242073A (en) * 1989-08-23 1993-09-07 Aluminum Company Of America Resealable container closure
US4953564A (en) * 1989-08-23 1990-09-04 Medtronic, Inc. Screw-in drug eluting lead
DE69029735T2 (de) * 1989-09-15 1997-07-31 Chiron Vision Corp Synthetisches material, das die anlagerung, das wachstum und die befestigung von epithelzellen fördert, prosthetische vorrichtung zur subepithelialen implantation sowie behandelte linse
US5153174A (en) * 1989-10-30 1992-10-06 Union Carbide Chemicals & Plastics Inc. Polymer mixtures useful in skin care
US5255693A (en) * 1989-11-02 1993-10-26 Possis Medical, Inc. Cardiac lead
US5217028A (en) * 1989-11-02 1993-06-08 Possis Medical, Inc. Bipolar cardiac lead with drug eluting device
US5525348A (en) * 1989-11-02 1996-06-11 Sts Biopolymers, Inc. Coating compositions comprising pharmaceutical agents
US5407683A (en) * 1990-06-01 1995-04-18 Research Corporation Technologies, Inc. Pharmaceutical solutions and emulsions containing taxol
US5833665A (en) * 1990-06-14 1998-11-10 Integra Lifesciences I, Ltd. Polyurethane-biopolymer composite
US5594158A (en) * 1990-06-22 1997-01-14 The Board Of Regents Of The University Of Nebraska Processes for producing doxorubicin, daunomycinone, and derivatives of doxorubicin
US5143724A (en) * 1990-07-09 1992-09-01 Biomatrix, Inc. Biocompatible viscoelastic gel slurries, their preparation and use
US5246698A (en) * 1990-07-09 1993-09-21 Biomatrix, Inc. Biocompatible viscoelastic gel slurries, their preparation and use
PH31064A (en) * 1990-09-07 1998-02-05 Nycomed As Of Nycoveten Polymers containing diester units.
WO1992006701A1 (en) * 1990-10-18 1992-04-30 Huffstutler, M., Conrad, Jr. Preparation of concentrated fluid symphytum extracts, therapeutic forms and methods of use
US5145684A (en) * 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
US5399363A (en) * 1991-01-25 1995-03-21 Eastman Kodak Company Surface modified anticancer nanoparticles
US5378475A (en) * 1991-02-21 1995-01-03 University Of Kentucky Research Foundation Sustained release drug delivery devices
US5520664A (en) * 1991-03-01 1996-05-28 Spire Corporation Catheter having a long-lasting antimicrobial surface treatment
GB9106678D0 (en) * 1991-03-28 1991-05-15 Ferguson Mark W J Wound healing
FR2678833B1 (fr) * 1991-07-08 1995-04-07 Rhone Poulenc Rorer Sa Nouvelles compositions pharmaceutiques a base de derives de la classe des taxanes.
ATE156368T1 (de) * 1991-12-06 1997-08-15 North Shore Univ Hospital Verfahren zum vermindern von durch medizinische vorrichtungen bedingten infektionen
GB9204918D0 (en) * 1992-03-06 1992-04-22 Nycomed As Chemical compounds
US5301664A (en) * 1992-03-06 1994-04-12 Sievers Robert E Methods and apparatus for drug delivery using supercritical solutions
AU3943793A (en) * 1992-04-01 1993-11-08 Whittier Institute For Diabetes And Endocrinology, The Methods of inhibiting or enhancing scar formation in the CNS
US5324324A (en) * 1992-10-13 1994-06-28 Siemens Pacesetter, Inc. Coated implantable stimulation electrode and lead
FR2698543B1 (fr) * 1992-12-02 1994-12-30 Rhone Poulenc Rorer Sa Nouvelles compositions à base de taxoides.
US5439686A (en) * 1993-02-22 1995-08-08 Vivorx Pharmaceuticals, Inc. Methods for in vivo delivery of substantially water insoluble pharmacologically active agents and compositions useful therefor
US5716981A (en) * 1993-07-19 1998-02-10 Angiogenesis Technologies, Inc. Anti-angiogenic compositions and methods of use
DK1159974T3 (da) * 1993-07-19 2007-11-26 Angiotech Pharm Inc Antiangiogene sammensætninger indeholdende taxol og en ikke-bionedbrydelig bærer og deres anvendelse
US20030203976A1 (en) * 1993-07-19 2003-10-30 William L. Hunter Anti-angiogenic compositions and methods of use
JPH0763933A (ja) * 1993-08-25 1995-03-10 Ricoh Co Ltd 光集積回路
US6361526B1 (en) * 1993-11-01 2002-03-26 Medtronic Xomed, Inc. Antimicrobial tympanostomy tube
CA2178620A1 (en) * 1993-12-08 1995-06-15 Lisa B. Jungherr Microsphere drug delivery system
AU1684595A (en) * 1994-01-21 1995-08-08 Brown University Research Foundation Biocompatible implants
JP3221210B2 (ja) * 1994-02-07 2001-10-22 富士ゼロックス株式会社 インクタンク
US5407633A (en) * 1994-03-15 1995-04-18 U.S. Philips Corporation Method of manufacturing a dispenser cathode
US5522874A (en) * 1994-07-28 1996-06-04 Gates; James T. Medical lead having segmented electrode
US5509899A (en) * 1994-09-22 1996-04-23 Boston Scientific Corp. Medical device with lubricious coating
US5562652A (en) * 1994-10-07 1996-10-08 Davis; William M. Antiseptic medical apparatus
US6351780B1 (en) * 1994-11-21 2002-02-26 Cirrus Logic, Inc. Network controller using held data frame monitor and decision logic for automatically engaging DMA data transfer when buffer overflow is anticipated
US5869127A (en) * 1995-02-22 1999-02-09 Boston Scientific Corporation Method of providing a substrate with a bio-active/biocompatible coating
US6179817B1 (en) * 1995-02-22 2001-01-30 Boston Scientific Corporation Hybrid coating for medical devices
US5624704A (en) * 1995-04-24 1997-04-29 Baylor College Of Medicine Antimicrobial impregnated catheters and other medical implants and method for impregnating catheters and other medical implants with an antimicrobial agent
US7611533B2 (en) * 1995-06-07 2009-11-03 Cook Incorporated Coated implantable medical device
US5609629A (en) * 1995-06-07 1997-03-11 Med Institute, Inc. Coated implantable medical device
CA2178541C (en) * 1995-06-07 2009-11-24 Neal E. Fearnot Implantable medical device
US5709672A (en) * 1995-11-01 1998-01-20 Texas Tech University Health Sciences Center Silastic and polymer-based catheters with improved antimicrobial/antifungal properties
EP0861570B1 (en) * 1995-11-13 2005-08-10 Cochlear Limited Implantable microphone for cochlear implants
CH691053A5 (fr) * 1995-11-24 2001-04-12 New Scaph Technology Sa Appareillage de plongée autonome.
US5987746A (en) * 1996-02-21 1999-11-23 Medtronic, Inc. Method of making medical electrical lead
US5942555A (en) * 1996-03-21 1999-08-24 Surmodics, Inc. Photoactivatable chain transfer agents and semi-telechelic photoactivatable polymers prepared therefrom
US6132765A (en) * 1996-04-12 2000-10-17 Uroteq Inc. Drug delivery via therapeutic hydrogels
CA2265670A1 (en) * 1996-09-12 1998-03-19 Vladimir P. Torchilin Nucleosome-based anti-tumor compositions
US5800412A (en) * 1996-10-10 1998-09-01 Sts Biopolymers, Inc. Hydrophilic coatings with hydrating agents
US6106473A (en) * 1996-11-06 2000-08-22 Sts Biopolymers, Inc. Echogenic coatings
JP3541913B2 (ja) * 1996-11-27 2004-07-14 株式会社デンソー 非水電解液二次電池
US6515016B2 (en) * 1996-12-02 2003-02-04 Angiotech Pharmaceuticals, Inc. Composition and methods of paclitaxel for treating psoriasis
US6495579B1 (en) * 1996-12-02 2002-12-17 Angiotech Pharmaceuticals, Inc. Method for treating multiple sclerosis
US20030157187A1 (en) * 1996-12-02 2003-08-21 Angiotech Pharmaceuticals, Inc. Compositions and methods for treating or preventing inflammatory diseases
US5729205A (en) * 1997-03-07 1998-03-17 Hyundai Motor Company Automatic transmission system of an emergency signal and a method thereof using a driver's brain wave
UA54505C2 (uk) * 1997-04-03 2003-03-17 Гілфорд Фармасьютікалз Інк. Полімери, що біологічно розкладаються, зшиті фосфатами, композиції, вироби і способи для їх виготовлення і використання
BR9809064A (pt) * 1997-04-03 2002-01-02 Guilford Pharm Inc Polìmeros biodegradáveis de poliéster de tereftalato-polifosfato, composições, artigos e métodos para fazer e usar os mesmos
US5912225A (en) * 1997-04-14 1999-06-15 Johns Hopkins Univ. School Of Medicine Biodegradable poly (phosphoester-co-desaminotyrosyl L-tyrosine ester) compounds, compositions, articles and methods for making and using the same
PL336596A1 (en) * 1997-04-30 2000-07-03 Guilford Pharm Inc Biodegradable compositions with polycycloaliphatic phosphoesters, products containing them and methods of using them
US6869938B1 (en) * 1997-06-17 2005-03-22 Fziomed, Inc. Compositions of polyacids and polyethers and methods for their use in reducing adhesions
DE69839077T2 (de) * 1997-06-18 2009-01-22 Boston Scientific Ltd., St. Michael Polycarbonat-polyurethan-dispersion als gerinnungsbeständige beschichtung
US6110483A (en) * 1997-06-23 2000-08-29 Sts Biopolymers, Inc. Adherent, flexible hydrogel and medicated coatings
US6121027A (en) * 1997-08-15 2000-09-19 Surmodics, Inc. Polybifunctional reagent having a polymeric backbone and photoreactive moieties and bioactive groups
US5854382A (en) * 1997-08-18 1998-12-29 Meadox Medicals, Inc. Bioresorbable compositions for implantable prostheses
US6119028A (en) * 1997-10-20 2000-09-12 Alfred E. Mann Foundation Implantable enzyme-based monitoring systems having improved longevity due to improved exterior surfaces
US6221425B1 (en) * 1998-01-30 2001-04-24 Advanced Cardiovascular Systems, Inc. Lubricious hydrophilic coating for an intracorporeal medical device
US6295474B1 (en) * 1998-03-13 2001-09-25 Intermedics Inc. Defibrillator housing with conductive polymer coating
US20020138123A1 (en) * 1998-04-21 2002-09-26 Medtronic, Inc. Medical electrical leads and indwelling catheters with enhanced biocompatibility and biostability
AU760408B2 (en) * 1998-04-27 2003-05-15 Surmodics, Inc. Bioactive agent release coating
US5916913A (en) * 1998-08-03 1999-06-29 Joseph; Hazel L. Inhibition of wound contraction with paclitaxel, colchicine and penicillamine
CA2340652C (en) * 1998-08-20 2013-09-24 Cook Incorporated Coated implantable medical device comprising paclitaxel
US6335029B1 (en) * 1998-08-28 2002-01-01 Scimed Life Systems, Inc. Polymeric coatings for controlled delivery of active agents
US6347379B1 (en) * 1998-09-25 2002-02-12 Intel Corporation Reducing power consumption of an electronic device
US6153212A (en) * 1998-10-02 2000-11-28 Guilford Pharmaceuticals Inc. Biodegradable terephthalate polyester-poly (phosphonate) compositions, articles, and methods of using the same
US6363387B1 (en) * 1998-10-20 2002-03-26 Sybase, Inc. Database system providing methodology for enhancing concurrency using row update bit and deferred locking
US6356788B2 (en) * 1998-10-26 2002-03-12 Birinder Bob Boveja Apparatus and method for adjunct (add-on) therapy for depression, migraine, neuropsychiatric disorders, partial complex epilepsy, generalized epilepsy and involuntary movement disorders utilizing an external stimulator
US6361780B1 (en) * 1998-11-12 2002-03-26 Cardiac Pacemakers, Inc. Microporous drug delivery system
US20020065546A1 (en) * 1998-12-31 2002-05-30 Machan Lindsay S. Stent grafts with bioactive coatings
US6197817B1 (en) * 1999-01-22 2001-03-06 Selectus Pharmaceuticals, Inc. Phenylpropionic acids and esters: compounds and methods for inducing beta-blockade for the treatment of cardiac disorders
UA71945C2 (en) * 1999-01-27 2005-01-17 Pfizer Prod Inc Substituted bicyclic derivatives being used as anticancer agents
US6333347B1 (en) * 1999-01-29 2001-12-25 Angiotech Pharmaceuticals & Advanced Research Tech Intrapericardial delivery of anti-microtubule agents
US6176817B1 (en) * 1999-08-24 2001-01-23 Anthony B. Carey Exercise and therapy device and method of making same
US6385491B1 (en) * 1999-10-04 2002-05-07 Medtronic, Inc. Temporary medical electrical lead having biodegradable electrode mounting pad loaded with therapeutic drug
US6335229B1 (en) * 1999-10-13 2002-01-01 International Business Machines Corporation Inductive fuse for semiconductor device
US6363287B1 (en) * 1999-10-27 2002-03-26 Medtronic, Inc. Steroid elution electrodes LVCV, left atrial medical/elecrical leads
WO2001036007A2 (en) * 1999-11-12 2001-05-25 Angiotech Pharmaceuticals, Inc. Compositions of a combination of radioactive therapy and cell-cycle inhibitors
US20030144570A1 (en) * 1999-11-12 2003-07-31 Angiotech Pharmaceuticals, Inc. Compositions and methods for treating disease utilizing a combination of radioactive therapy and cell-cycle inhibitors
US6970742B2 (en) * 2000-01-11 2005-11-29 Savacor, Inc. Method for detecting, diagnosing, and treating cardiovascular disease
US6403618B1 (en) * 2000-02-15 2002-06-11 Novactyl, Inc. Agent and method for controlling angiogenesis
US20030008588A1 (en) * 2000-03-03 2003-01-09 Gregor Kohlruss Textile skin cleaning device
US20010049422A1 (en) * 2000-04-14 2001-12-06 Phaneuf Matthew D. Methods of applying antibiotic compounds to polyurethane biomaterials using textile dyeing technology
US20020026244A1 (en) * 2000-08-30 2002-02-28 Trieu Hai H. Intervertebral disc nucleus implants and methods
US7304122B2 (en) * 2001-08-30 2007-12-04 Cornell Research Foundation, Inc. Elastomeric functional biodegradable copolyester amides and copolyester urethanes
US6716444B1 (en) * 2000-09-28 2004-04-06 Advanced Cardiovascular Systems, Inc. Barriers for polymer-coated implantable medical devices and methods for making the same
US20020111590A1 (en) * 2000-09-29 2002-08-15 Davila Luis A. Medical devices, drug coatings and methods for maintaining the drug coatings thereon
MXPA03002871A (es) * 2000-09-29 2004-12-06 Johnson & Johnson Dispositivos medicos recubiertos.
US20050084514A1 (en) * 2000-11-06 2005-04-21 Afmedica, Inc. Combination drug therapy for reducing scar tissue formation
US20060286063A1 (en) * 2000-11-06 2006-12-21 Afmedica, Inc. Combination drug therapy for reducing scar tissue formation
US20040018228A1 (en) * 2000-11-06 2004-01-29 Afmedica, Inc. Compositions and methods for reducing scar tissue formation
US20040241211A9 (en) * 2000-11-06 2004-12-02 Fischell Robert E. Devices and methods for reducing scar tissue formation
AUPR148400A0 (en) * 2000-11-14 2000-12-07 Cochlear Limited Apparatus for delivery of pharmaceuticals to the cochlea
AR035531A1 (es) * 2001-01-22 2004-06-02 Novartis Ag Composicion para el control de plagas endoparasiticas en ganados y animales domesticos, un metodo para su control y el uso de dicha composicion para la preparacion de medicamentos
US6952613B2 (en) * 2001-01-31 2005-10-04 Medtronic, Inc. Implantable gastrointestinal lead with active fixation
GB0103668D0 (en) * 2001-02-15 2001-03-28 Biointeractions Ltd Methods and clinical devices for the inhibition or prevention of mammalian cell growth
EP1256573A1 (en) * 2001-05-09 2002-11-13 Eisai Co., Ltd. Process for producing stereoisomer of pyrrolidine derivative
JP3495348B2 (ja) * 2001-07-02 2004-02-09 日本コーリン株式会社 脈波伝播速度情報測定装置
IN2014DN10834A (US20050142162A1-20050630-C00074.png) * 2001-09-17 2015-09-04 Psivida Inc
US20030229390A1 (en) * 2001-09-17 2003-12-11 Control Delivery Systems, Inc. On-stent delivery of pyrimidines and purine analogs
US20030158598A1 (en) * 2001-09-17 2003-08-21 Control Delivery Systems, Inc. System for sustained-release delivery of anti-inflammatory agents from a coated medical device
TWI261053B (en) * 2001-12-06 2006-09-01 Novartis Ag Amidoacetonitrile compounds, their preparation, compositions and use as pesticides
US20030216758A1 (en) * 2001-12-28 2003-11-20 Angiotech Pharmaceuticals, Inc. Coated surgical patches
AR038156A1 (es) * 2002-01-21 2004-12-29 Novartis Ag Compuestos de amidoacetonitrilo, proceso para su preparacion, composicion para controlar los parasitos, y uso de estos compuestos para preparar una composicion farmaceutica
WO2003065881A2 (en) * 2002-02-06 2003-08-14 Orbus Medical Technologies Inc. Medical device with coating that promotes endothelial cell adherence and differentiation
AU2002367730A1 (en) * 2002-02-26 2003-09-09 Stephen L. Schlesinger Use of leukotriene receptor antagonist for treatment of scarring
CA2480832A1 (en) * 2002-04-05 2003-10-23 Nitromed, Inc. Nitric oxide donors, compositions and methods of use
US6969369B2 (en) * 2002-04-22 2005-11-29 Medtronic, Inc. Implantable drug delivery system responsive to intra-cardiac pressure
US7153265B2 (en) * 2002-04-22 2006-12-26 Medtronic Minimed, Inc. Anti-inflammatory biosensor for reduced biofouling and enhanced sensor performance
US7008979B2 (en) * 2002-04-30 2006-03-07 Hydromer, Inc. Coating composition for multiple hydrophilic applications
US20030208166A1 (en) * 2002-05-06 2003-11-06 Schwartz Anthony H. Implantable device with free-flowing exit and uses thereof
TW200400931A (en) * 2002-05-22 2004-01-16 Novartis Ag Organic compounds
CN100341589C (zh) * 2002-05-24 2007-10-10 血管技术国际股份公司 用于涂覆医用植入物的组合物和方法
US8211455B2 (en) * 2002-06-19 2012-07-03 Boston Scientific Scimed, Inc. Implantable or insertable medical devices for controlled delivery of a therapeutic agent
US7622146B2 (en) * 2002-07-18 2009-11-24 Advanced Cardiovascular Systems, Inc. Rate limiting barriers for implantable devices and methods for fabrication thereof
AR042420A1 (es) * 2002-09-11 2005-06-22 Novartis Ag Benzotriazolil- aminoacetonitril compuestos, proceso para su preparacion, metodo y uso de los mismos en el control de endo- y ecto-parasitos dentro y sobre ganado productor de sangre caliente y animales domesticos y plantas, y en la preparacion de una composicion farmaceutica
US6770729B2 (en) * 2002-09-30 2004-08-03 Medtronic Minimed, Inc. Polymer compositions containing bioactive agents and methods for their use
US9060844B2 (en) * 2002-11-01 2015-06-23 Valentx, Inc. Apparatus and methods for treatment of morbid obesity
US6896965B1 (en) * 2002-11-12 2005-05-24 Advanced Cardiovascular Systems, Inc. Rate limiting barriers for implantable devices
US7282214B2 (en) * 2002-12-19 2007-10-16 Johnson & Johnson Vision Care, Inc. Biomedical devices with antimicrobial coatings
EP1583561A3 (en) * 2002-12-30 2005-12-07 Angiotech International Ag Tissue reactive compounds and compositions and uses thereof
AU2003300076C1 (en) * 2002-12-30 2010-03-04 Angiotech International Ag Drug delivery from rapid gelling polymer composition
EP1601353A4 (en) * 2003-01-29 2008-08-13 Childrens Medical Center PREVENT OPERATIONAL ADVANCES WITH SELECTIVE COX-2 INHIBITORS
WO2004079129A1 (en) * 2003-03-07 2004-09-16 Akzo Nobel Coatings International B.V. Interlocking unit
US7306580B2 (en) * 2003-04-16 2007-12-11 Cook Incorporated Medical device with therapeutic agents
US8696564B2 (en) * 2004-07-09 2014-04-15 Cardiac Pacemakers, Inc. Implantable sensor with biocompatible coating for controlling or inhibiting tissue growth

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5411527A (en) * 1989-05-03 1995-05-02 Intermedics, Inc. Difibrillation electrodes and implantation
WO2002036054A1 (en) * 2000-11-06 2002-05-10 Afmedica, Inc. Surgically implanted devices having reduced scar tissue
US20030068297A1 (en) * 2001-08-18 2003-04-10 Deepak Jain Composition and methods for skin rejuvenation and repair

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11439817B2 (en) 2009-08-03 2022-09-13 Incube Labs, Llc Swallowable capsule and method for stimulating incretin production within the intestinal tract
US11872396B2 (en) 2009-08-03 2024-01-16 Incube Labs, Llc Swallowable capsule and method for stimulating incretin production within the intestinal tract
US10603475B2 (en) 2009-12-24 2020-03-31 Rani Therapeutics, Llc Swallowable drug delivery device and methods of drug delivery
US10987499B2 (en) 2009-12-24 2021-04-27 Rani Therapeutics, Llc Swallowable drug delivery device and method of delivery
US11376405B2 (en) 2009-12-24 2022-07-05 Rani Therapeutics, Llc Therapeutic agent preparations into a lumen of the intestinal tract using a swallowable drug delivery device
US11338118B2 (en) 2009-12-24 2022-05-24 Rani Therapeutics, Llc Swallowable drug delivery device and methods of drug delivery
US10493253B2 (en) 2009-12-24 2019-12-03 Rani Therapeutics, Llc Therapeutic agent preparations into a lumen of the intestinal tract using a swallowable drug delivery device
US11253686B2 (en) 2009-12-24 2022-02-22 Rani Therapeutics, Llc Swallowable drug delivery device and methods of drug delivery
US10596359B2 (en) 2009-12-24 2020-03-24 Rani Therapeutics, Llc Therapeutic agent preparations into a lumen of the intestinal tract using a swallowable drug delivery device
US10252039B2 (en) 2009-12-24 2019-04-09 Rani Therapeutics, Llc Therapeutic agent preparations into a lumen of the intestinal tract using a swallowable drug delivery device
US10487145B2 (en) 2010-12-23 2019-11-26 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US11304895B2 (en) 2010-12-23 2022-04-19 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10752681B2 (en) 2010-12-23 2020-08-25 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10864254B2 (en) 2010-12-23 2020-12-15 Rani Therapeutics, Llc Method of delivering gonadotropin releasing hormone or an analogue thereof into a lumen of the intestinal tract using a swallowable drug delivery device
US10874840B2 (en) 2010-12-23 2020-12-29 Rani Therapeutics, Llc Preparation comprising exanatide for delivery into a lumen of the intestinal tract
US10888517B2 (en) 2010-12-23 2021-01-12 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10926073B2 (en) 2010-12-23 2021-02-23 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10953077B2 (en) 2010-12-23 2021-03-23 Rani Therapeutics, Llc Method of delivering a somatostatin compound into a lumen of the intestinal tract using a swallowable drug delivery device
US10478396B2 (en) 2010-12-23 2019-11-19 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10632251B2 (en) 2010-12-23 2020-04-28 Rani Therapeutics, Llc Device, system and methods for the oral delivery of therapeutic compounds
US10350163B2 (en) 2010-12-23 2019-07-16 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US11229684B2 (en) 2010-12-23 2022-01-25 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10548850B2 (en) 2010-12-23 2020-02-04 Rani Therapeutics, Llc Therapeutic composition comprising insulin prepared for delivery into an intestinal tract
US10639272B2 (en) 2010-12-23 2020-05-05 Rani Therapeutics, Llc Methods for delivering etanercept preparations into a lumen of the intestinal tract using a swallowable drug delivery device
US10980749B2 (en) 2010-12-23 2021-04-20 Rani Therapeutics, Llc Therapeutic preparation comprising insulin for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10967050B2 (en) 2010-12-23 2021-04-06 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US11419812B2 (en) 2010-12-23 2022-08-23 Rani Therapeutics, Llc Methods for delivering etanercept preparations into a lumen of the intestinal tract using a swallowable drug delivery device
US10335463B2 (en) 2010-12-23 2019-07-02 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US11555068B2 (en) 2010-12-23 2023-01-17 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US11638690B2 (en) 2010-12-23 2023-05-02 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US11654182B2 (en) 2010-12-23 2023-05-23 Rani Therapeutics, Llc Method of delivering gonadotropin releasing hormone or an analogue thereof into a lumen of the intestinal tract using a swallowable drug delivery device
US11684761B2 (en) 2010-12-23 2023-06-27 Rani Therapeutics, Llc Preparation comprising exanatide for delivery into a lumen of the intestinal tract
US11771879B2 (en) 2010-12-23 2023-10-03 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US11806504B2 (en) 2010-12-23 2023-11-07 Rani Therapeutics, Llc Device, system and methods for the oral delivery of therapeutic compounds
US11813314B2 (en) 2010-12-23 2023-11-14 Rani Therapeutics, Llc Method of delivering a somatostatin compound into a lumen of the intestinal tract using a swallowable drug delivery device
US11814427B2 (en) 2010-12-23 2023-11-14 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US11844867B2 (en) 2010-12-23 2023-12-19 Rani Therapeutics, Llc Method of delivering insulin into a lumen of the intestinal tract using a swallowable drug delivery device
US10307579B2 (en) 2010-12-23 2019-06-04 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device

Also Published As

Publication number Publication date
WO2005051871A2 (en) 2005-06-09
US20050181007A1 (en) 2005-08-18
US20050152948A1 (en) 2005-07-14
US20050192647A1 (en) 2005-09-01
WO2005051871A8 (en) 2005-08-25
WO2006055008A3 (en) 2009-04-16
US20050152947A1 (en) 2005-07-14
US20050152944A1 (en) 2005-07-14
US20050182450A1 (en) 2005-08-18
CA2536192A1 (en) 2005-06-09
JP2007514472A (ja) 2007-06-07
US20050203635A1 (en) 2005-09-15
WO2005051451A2 (en) 2005-06-09
CA2536188A1 (en) 2005-06-09
JP2007513650A (ja) 2007-05-31
US20100268288A1 (en) 2010-10-21
WO2005051871A9 (en) 2006-07-27
US20050209666A1 (en) 2005-09-22
EP1685085A2 (en) 2006-08-02
US20050181005A1 (en) 2005-08-18
EP1687041A2 (en) 2006-08-09
CA2536242A1 (en) 2005-06-09
US20050154374A1 (en) 2005-07-14
US20050186239A1 (en) 2005-08-25
US20050142162A1 (en) 2005-06-30
WO2005051232A2 (en) 2005-06-09
US20050187639A1 (en) 2005-08-25
US20050181009A1 (en) 2005-08-18
WO2006055008A2 (en) 2006-05-26
AU2004293075A1 (en) 2005-06-09
US20050186245A1 (en) 2005-08-25
AU2004293030A1 (en) 2005-06-09
US20050182467A1 (en) 2005-08-18
US20100092536A1 (en) 2010-04-15
WO2005051444A2 (en) 2005-06-09
US20050182496A1 (en) 2005-08-18
US20050182468A1 (en) 2005-08-18
WO2005051451A8 (en) 2005-10-27
US20050149157A1 (en) 2005-07-07
US20050152946A1 (en) 2005-07-14
US20050158356A1 (en) 2005-07-21
US20050169960A1 (en) 2005-08-04
WO2005051483A3 (en) 2005-07-07
US20050175664A1 (en) 2005-08-11
US20050181010A1 (en) 2005-08-18
US20050169961A1 (en) 2005-08-04
US20060282123A1 (en) 2006-12-14
US20050187600A1 (en) 2005-08-25
US20050186246A1 (en) 2005-08-25
US20050152941A1 (en) 2005-07-14
US20050182469A1 (en) 2005-08-18
US20050152945A1 (en) 2005-07-14
WO2005051232A3 (en) 2005-12-08
US20050209665A1 (en) 2005-09-22
AU2004293463A1 (en) 2005-06-09
JP2007516742A (ja) 2007-06-28
WO2005051483A2 (en) 2005-06-09
US20090214652A1 (en) 2009-08-27

Similar Documents

Publication Publication Date Title
US20050182469A1 (en) Electrical devices and anti-scarring agents
US20050209664A1 (en) Electrical devices and anti-scarring agents

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20060321

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LU MC NL PL PT RO SE SI SK TR

DAX Request for extension of the european patent (deleted)
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1093922

Country of ref document: HK

17Q First examination report despatched

Effective date: 20140828

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1093922

Country of ref document: HK

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20170301